Rozenta

Tablet: Each film-coated tablet contains: Azithromycin Dihydrate USP eq. to anhydrous Azithromycin 500 mg.
Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C₃₈H₇₂N₂O₁₂·2H₂O and a molecular weight of 785.0.
Suspension: White-colored free flowing powder with mint odour.
After reconstitution: White homogenous suspension with mint odour.
Each 5 mL (after reconstitution) contains: Azithromycin USP (As Dihydrate) Equivalent to Azithromycin (Anhydrous) 200mg.
Excipients/Inactive Ingredients: Tablet: Pregelatinized starch, calcium phosphate dibasic anhydrous, croscarmellose sodium, magnesium stearate and sodium lauryl sulfate. The film coating contains hydroxypropyl methylcellulose, triacetin and titanium dioxide (E171).

Pharmacotherapeutic group: Antibacterials for systemic use; macrolides; azithromycin. ATC code: J01FA10.
Pharmacology: Pharmacodynamics: Tablet: Mode of action: Azithromycin is an azalide, a sub-class of the macrolide antibiotics. By binding to the 50S ribosomal 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.
PK/PD relationship: For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.
Mechanism of resistance: Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.
Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.
Suspension: Mechanism of Action: Azithromycin is the first of a subclass of macrolide antibiotics, known as azalides, and is chemically different from erythromycin. Chemically it is derived by the 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. Azithromycin binds to the 23S rRNA of the 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.
Cardiac electrophysiology: QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with azithromycin (500 mg, 1,000 mg, and 1,500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms, and 9 (14) ms with the co-administration of 500 mg, 1,000 mg, and 1,500 mg azithromycin, respectively.
Mechanism of resistance: The two most frequently encountered mechanisms of resistance to macrolides, including azithromycin, are target modification (most often by methylation of 23S rRNA) and active efflux. The occurrence of these resistance mechanisms varies from species to species and, within a species, the frequency of resistance varies by geographical location. The most important ribosomal modification that determines reduced binding of macrolides is post-transcriptional (N6)-dimethylation of adenine at nucleotide A2058 (Escherichia coli numbering system) of the 23S rRNA by methylases encoded by erythromycin ribosome methylase (erm) genes. Ribosomal modifications often determine cross-resistance (MLSB phenotype) to other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin), and the streptogramin B (which include, for example, the quinupristin component of quinupristin/dalfopristin). Different erm genes are present in different bacterial species, in particular streptococci and staphylococci. Susceptibility to macrolides can also be affected by less frequently encountered mutational changes in nucleotides A2058 and A2059, and at some other positions of 23S rRNA, or in the large subunit ribosomal proteins L4 and L22. Efflux pumps occur in a number of species, including gram-negatives, such as Haemophilus influenzae (where they may determine intrinsically higher minimal inhibitory concentrations [MICs]) and staphylococci. In streptococci and enterococci, an efflux pump that recognizes 14- and 15-membered macrolides (which include, respectively, erythromycin and azithromycin) is encoded by mef (A) genes.
Methodology for determining the in vitro susceptibility of bacteria to azithromycin: Susceptibility testing should be conducted using standardized laboratory methods, such as those described by the Clinical and Laboratory Standards Institute (CLSI). These include dilution methods (MIC determination) and disk susceptibility methods. Both CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) provide interpretive criteria for these methods. Based on a number of studies, it is recommended that the in vitro activity of azithromycin be tested in ambient air to ensure the physiological pH of the growth medium. Elevated CO2 tensions, as often used for streptococci and anaerobes, and occasionally for other species, result in a reduction in the pH of the medium. This has a greater adverse effect on the apparent potency of azithromycin than on that of other macrolides. The CLSI susceptibility breakpoints, based on broth microdilution or agar dilution testing, with incubation in ambient air, are given in the table as follows. (See Table 1.)

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Susceptibility can also be determined by the disk diffusion method, measuring inhibition zone diameters after incubation in ambient air. Susceptibility disks contain 15 μg of azithromycin. Interpretive criteria for inhibition zones, established by the CLSI on the basis of their correlation with MIC susceptibility categories, are listed in the table as follows. (See Table 2.)

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The validity of both the dilution and disk diffusion test methods should be verified using quality control (QC) strains, as indicated by the CLSI. Acceptable limits when testing azithromycin against these organisms are listed in the table as follows. (See Table 3.)

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EUCAST has also established susceptibility breakpoints for azithromycin based on MIC determination. The EUCAST susceptibility criteria are listed in the table as follows. (See Table 4.)

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Antibacterial spectrum: 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. Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive isolates. As discussed previously, some ribosomal modifications determine cross-resistance with other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin) and the streptogramin B (which include, for example, the quinupristin component of quinupristin/dalfopristin). A decrease in macrolide susceptibility over time has been noted in particular in Streptococcus pneumoniae and Staphylococcus aureus, and has also been observed in viridans streptococci and Streptococcus agalactiae.
Organisms that are commonly susceptible to azithromycin include: Aerobic and facultative gram-positive bacteria (erythromycin-susceptible isolates): S. aureus, S. agalactiae,* S. pneumoniae,* S. pyogenes,* other β-hemolytic streptococci (Groups C, F, G), and viridans streptococci. Macrolide-resistant isolates are encountered relatively frequently among aerobic and facultative gram-positive bacteria, in particular among methicillin-resistant S. aureus (MRSA) and penicillin-resistant S. pneumoniae (PRSP).
Aerobic and facultative gram-negative bacteria: Bordetella pertussis, Campylobacter jejuni, Haemophilus ducreyi,* Haemophilus influenzae,* Haemophilus parainfluenzae,* Legionella pneumophila, Moraxella catarrhalis,* and Neisseria gonorrhoeae*. Pseudomonas spp. and most Enterobacteriaceae are inherently resistant to azithromycin, although azithromycin has been used to treat Salmonella enterica infections.
Anaerobes: Clostridium perfringens, Peptostreptococcus spp. and Prevotella bivia.
Other bacterial species: Borrelia burgdorferi, Chlamydia trachomatis, Chlamydophila pneumoniae,* Mycoplasma pneumoniae,* Treponema pallidum, and Ureaplasma urealyticum.
Opportunistic pathogens associated with HIV infection: MAC* and the eukaryotic microorganisms Pneumocystis jirovecii and Toxoplasma gondii.
*The efficacy of azithromycin against the indicated species has been demonstrated in clinical trials.
Pharmacokinetics: Tablet: 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: Kinetic studies have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady state distribution volume of approximately 31 L/kg). Concentrations in target tissues such as lungs, tonsil, and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.
In experimental in vitro and in vivo studies azithromycin accumulates in the phagocytes, freeing is stimulated by active phagocytosis. In animal studies this process appeared to contribute to the accumulation of azithromycin in the tissue.
In serum the protein binding of azithromycin is variable and depending on the serum concentration varies from 50% in 0.05 mg/L to 12% in 0.5 mg/L.
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.
Pharmacokinetics in special populations: Renal insufficiency: Following a single oral dose of azithromycin 1 g, mean Cmax and AUC0-120 increased 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 >80 mL/min). In subjects with severe renal impairment, the mean Cmax and AUC0-120 increased 61% and 33% 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.
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 Cmax achieved is slightly lower than adults with 224 μg/L in children aged 0.6-5 years and after 3 days dosing and 383 μg/L in those aged 6-15 years. The t_1/2 of 36 h in the older children was within the expected range for adults.
Suspension: 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 to 3 hours.
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 tissues 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 the lungs, tonsil, and prostate, exceed the MIC90 for likely pathogens after a single dose of 500 mg. Following oral administration of daily doses of 600 mg azithromycin, Cmax was 0.33 μg/mL and 0.55 μg/mL on Day 1 and Day 22, respectively. Mean peak concentrations observed in leukocytes, the major site of disseminated MAC infection, were 252 μg/mL (± 49%) and remained above 146 μg/mL (± 33%) for 24 hours at steady state.
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 drugs 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, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. A 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 1 g dose of immediate-release azithromycin. Statistically significant differences in AUC0-120 (8.8 μg·h/mL vs. 11.7 μg·h/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.
Toxicology: Preclinical Safey Data: Suspension: 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 humans is unknown.

Azithromycin is indicated for infections caused by susceptible organisms; in lower respiratory tract infections including bronchitis and pneumonia, in skin and soft tissue infections, in acute otitis media and in upper respiratory tract infections including sinusitis and pharyngitis/tonsillitis. (Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin is generally effective in the eradication of streptococci from the oropharynx. However, data establishing the efficacy of azithromycin and the subsequent prevention of rheumatic fever are not available at present). In sexually transmitted diseases in men and women, azithromycin is indicated in the treatment of uncomplicated genital infections due to Chlamydia trachomatis.
It is also indicated in the treatment of chancroid due to Haemophilus ducreyi and uncomplicated genital infections due to non-multi resistant Neisseria gonorrhoeae; concurrent infection with Treponema pallidum should be excluded.
Azithromycin is indicated, either alone or in combination with rifabutin, for prophylaxis against Mycobacterium avium-intracellulare complex (MAC) infection, an opportunistic infection prevalent in patients with advanced human immunodeficiency virus (HIV). Azithromycin is indicated in combination with ethambutol for the treatment of disseminated MAC (DMAC) infection in patients with advanced HIV infection.

Oral azithromycin should be administered as a single daily dose. The period of dosing with regard to infection is given as follows.
Tablet: Azithromycin tablets should only be administered to children weighing more than 45 kg.
The safety and efficacy of intravenous azithromycin for the treatment of infections in children have not been established. Safety and efficacy for the prevention or treatment of MAC in children have not been established. Based on pediatric pharmacokinetic data, a dose of 20 mg/kg would be similar to the adult dose of 1,200 mg but with a ^higherCmax.
Elderly: The same dosage as in adult patients is used in the elderly. Elderly patients may be more susceptible to the development of Torsades de pointes arrhythmia than younger patients.
In 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).
In 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.
Or as prescribed by the physician.
Administration: Azithromycin tablets can be taken with or without food. The tablets should be swallowed whole.
Suspension: Azithromycin tablets, powder for oral suspension can be taken with or without food.
In adults: For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis and Hemophilus ducreyi, the dose is 1,000 mg as a single oral dose. For susceptible Neisseria gonorrhoeae, the recommended dose is 1,000 mg or 2,000 mg of azithromycin in combination with 250 mg or 500 mg of ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines. For prophylaxis against MAC infections in patients infected with HIV, the dose is 1,200 mg once per week. For the treatment of DMAC infections in patients with advanced HIV infection, the recommended dose is 600 mg once a day. Azithromycin should be administered in combination with other antimycobacterial agents that have shown in vitro activity against MAC, such as ethambutol, at the approved dose. For the treatment of adult patients with CAP due to the indicated organisms, the recommended dose of IV azithromycin is 500 mg as a single daily dose by the IV route for at least 2 days. IV 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 IV azithromycin is 500 mg as a single dose by the IV route for 1 or 2 days. IV therapy should be followed by oral azithromycin at a single daily dose of 250 mg to complete a 7-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. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial anaerobic agent may be administered in combination with azithromycin. For all other indications in which the oral formulation is administered, the total dosage of 1,500 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 25 mg daily on Days 2 to 5.
In children: The maximum recommended total dose for any treatment is 1,500 mg for children. In general, the total dose in children is 30 mg/kg. Treatment for pediatric streptococcal pharyngitis should be dosed at a different regimen (see as follows). The total dose of 30 mg/kg should be given as a single daily dose of 10 mg/kg daily for 3 days, or given over 5 days with a single daily dose of 10 mg/kg on Day 1, then 5 mg/kg on Days 2-5. As an alternative to the previously mentioned dosing, treatment for children with acute otitis media can be given as a single dose of 30 mg/kg. For pediatric streptococcal pharyngitis, azithromycin given as a single dose of 10 mg/kg or 20 mg/kg for 3 days has been shown to be effective; however, a daily dose of 500 mg must not be exceeded. In clinical trials comparing these two dosage regimens, similar clinical efficacy was observed but greater bacteriologic eradication was evident at the 20 mg/kg/day dose. However, penicillin is the usual drug of choice for the treatment of Streptococcus pyogenes pharyngitis, including prophylaxis of rheumatic fever.
For children weighing less than 15 kg, azithromycin suspension should be measured as closely as possible. For children weighing 15 kg or more, azithromycin suspension should be administered according to the guide provided as follows: (See Table 5.)

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Special populations: In the Elderly: The same dosage as in adult patients is used in the elderly. Elderly patients may be more susceptible to the development of Torsades de pointes arrhythmia than younger patients (see Precautions).
In 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 Precautions and Pharmacology: Pharmacokinetics under Actions).
In 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).

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.

The use of this product is contraindicated in patients with a hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic.
Tablet: Hypersensitivity to any excipient listed as follows: Pregelatinized starch, calcium phosphate dibasic anhydrous, croscarmellose sodium, magnesium stearate and sodium lauryl sulfate. The film coating contains hydroxypropyl methylcellulose, triacetin and titanium dioxide (E171).

Hypersensitivity: As with erythromycin and other macrolides, rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), Dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) (rarely fatal), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 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 the 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 death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
Ergot derivatives: In patients receiving ergot derivatives, ergotism has been precipitated by the 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.
Superinfection: As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
Clostridium Difficile-Associated Diarrhea: Clostridium difficile associated diarrhea (CDAD) has been reported with the 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 2 months after the administration of antibacterial agents.
Diabetes: Azithromycin 40 mg/mL Powder for Oral Suspension: Caution in diabetic patients: 5 mL of reconstituted suspension contains 3.87 g of sucrose.
Due to the sucrose content (3.87 g/5 mL of reconstituted suspension), this medicinal product is not indicated for persons with fructose intolerance (hereditary fructose intolerance), glucose-galactose malabsorption, or saccharase-isomaltase deficiency.
Prolongation of the 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 macrolides, including azithromycin (see Adverse Reactions). Prescribers should consider the risk of QT prolongation, which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including Patients with congenital or documented QT prolongation.
Patients currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of Classes IA and III, antipsychotic agents, antidepressants, and fluoroquinolones.
Patients with electrolyte disturbance, particularly in cases of hypokalemia and hypomagnesemia. Patients with clinically relevant bradycardia, cardiac arrhythmia, or cardiac insufficiency.
Effects 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.
Renal impairment: In patients with severe renal impairment (GFR <10 mL/min), a 33% increase in systemic exposure to azithromycin was observed (see Pharmacology: Pharmacokinetics under Actions).
Use in the Elderly: Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Suspension: Infantile hypertrophic pyloric stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.
Myasthenia gravis: Exacerbations of the symptoms of myasthenia gravis have been reported in patients receiving azithromycin therapy.

Pregnancy: 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.
Lactation: Tablet: 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.
Suspension: Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breastfed infants were observed. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility: In fertility studies conducted in rats, reduced pregnancy rates were noted following the 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) has 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.
The following undesirable effects have been reported in association with DMAC prophylaxis and treatment clinical trials: The most frequent (>5% in any treatment group) adverse reactions in HIV-infected patients receiving azithromycin for prophylaxis for DMAC were diarrhea, abdominal pain, nausea, loose stools, flatulence, vomiting, dyspepsia, rash, pruritus, headache, and arthralgia.
When azithromycin 600 mg is given daily for the treatment of DMAC infection for prolonged periods, the most frequently reported treatment-related side effects are abdominal pain, nausea, vomiting, diarrhea, flatulence, headache, abnormal vision, and hearing impairment.
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 Precautions).
Metabolism and Nutrition Disorders: Anorexia.
Psychiatric Disorders: Aggressive reaction, nervousness, agitation, and anxiety.
Nervous System Disorders: Dizziness, convulsions, headache, hyperactivity, hypoesthesia, paresthesia, somnolence, and syncope.
There have been rare reports of taste/smell perversion and/or loss.
Ear and Labyrinth Disorders: Deafness, tinnitus, hearing impaired, and 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 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 cholestatic jaundice have been reported, as well as rare cases of hepatic necrosis and hepatic failure, which have resulted in death (see Precautions).
Skin and Subcutaneous Tissue Disorders: Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria, and angioedema. Rarely, serious cutaneous adverse reactions including erythema multiforme, AGEP, SJS, TEN, and DRESS 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, fatigue, and malaise.

Suspension: Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacids with azithromycin, no effect on overall bioavailability was seen, although peak serum concentrations were reduced by approximately 24%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.
Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with 20 mg cetirizine at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (Dideoxyinosine): Co-administration of 1,200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared to placebo.
Digoxin and colchicine: Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-glycoprotein substrates, such as 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.
Ergot: There is a theoretical possibility of interaction between azithromycin and ergot derivatives (see Precautions).
Zidovudine: Single 1,000 mg doses and multiple 1,200 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 seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450-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 an 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 dose of 15 mg warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to the 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 who 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 considering concurrent administration of these drugs. If co-administration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz: Co-administration of a single dose of 600 mg azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole: Co-administration of a single dose of 1,200 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 co-administration of fluconazole; however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
Indinavir: Co-administration of a single dose of 1,200 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, co-administration of 500 mg/day azithromycin for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of 15 mg midazolam.
Nelfinavir: Co-administration of azithromycin (1,200 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 was 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 in combination with azithromycin has not been established (see Adverse Reactions).
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.
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 500 mg azithromycin 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: Co-administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with 1,200 mg azithromycin 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.

Tablet: The tablets should be swallowed whole.
Suspension: Direction for Reconstitution: Shake the bottle to loosen the powder, then add water up to the black arrow mark on the label and shake vigorously.
Adjust the volume to the mark by adding more water if necessary.
The reconstituted suspension should be stored below 30°C and consumed within 5 days. Discard unused suspensions.
Azithromycin tablets should only be administered to children weighing more than 45 kg. Safety and efficacy for the prevention or treatment of MAC in children have not been established. Based on pediatric pharmacokinetic data, a dose of 20 mg/kg would be similar to the adult dose of 1,200 mg but with a higher Cmax.

Store at a temperature not exceeding 30°C.
Tablet: Store in a dry place & protect from light.

Macrolides

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

Rx