Aziro-500

Azithromycin dihydrate.

Each film-coated tablet contains: Azithromycin dihydrate USP equivalent to Azithromycin 500 mg.
Azithromcyin Tablets, USP contain the active ingredient azithromycin, anazalide, a substance of macrolide antibiotics for oral administration. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromcyin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C₃₈H₇₂N₂O₁₂, and its molecular weight is 749.
Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula C₃₈H₇₂N₂O₁₂•2H₂O and a molecular weight of 785.
Azithromycin is supplied for oral administration as, white oval shape film-coated tablets with break line on one surface containing azithromycin dihydrate equivalent to 500 mg azithromycin.
Excipients/Inactive Ingredients: Microcrystalline Cellulose, Lactose, Maize starch, Purified talc, Colloidal anhydrous silica, Sodium starch glycolate, Croscarmellose sodium, magnesium stearate and Hypromellose, ethyl cellulose, polyethylene glycol, Titanium Dioxide, Sunset yellow lake, Isopropyl alcohol and Dichloromethane used as coating material.

Pharmacology: Azithromycin dihydrate, a macrolide of the azalide subclass, exerts its antibacterial action by binding to the 50s ribosomal subunit of susceptible bacteria and suppressing protein synthesis.
Pharmacokinetics: Azithromycin given orally is rapidly absorbed and about 40% bioavailable. Absorption from capsules, but not tablets or suspension, is reduced by food. Peak plasma concentrations occur 2 to 3 hours after an oral dose. However, Azithromycin is extensively distributed into the tissues, and tissue concentrations subsequently remain much higher than those in the blood; in contrast to most other antibacterials, plasma concentrations are therefore of little value as a guide to efficacy.
High concentrations are taken up into white blood cells. There is little diffusion into the CSF when the meninges are not inflamed. Data from animal studies indicate that azithromycin crosses the placenta. Small amounts of azithromycin are demethylated in the liver, and it is excreted in bile as unchanged drug and a number of inactive metabolites have also been detected. About 6% of an oral dose (representing about 20% of the amount in the systemic circulation) is excreted in the urine. The terminal elimination half-life is about 68 hours.
Microbiology: Antimicrobial activity: Azithromycin is less than erythromycin against streptococci and staphylococci, but has greater activity than erythromycin in vitro against some Gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis (Branhamella catarrhalis), as well as having activity against some of the Enterobacteriaceae such as Escherichia coli and Salmonella and Shigella spp. Azithromycin is also more active than erythromycin against Chlamydia trachomatis and Ureaplasma urealyticum, and some opportunistic mycobacteria, including Mycobacterium avium complex. It has activity against the protozoa Taxoplasma gondii and Plasmodium falciparum.

For the treatment of respiratory-tract infections (including otitis media), in skin and soft-tissue infections and in uncomplicated genital infections. Also used for the prophylaxis and as component of regimens in the treatment of Mycobacterium avium complex (MAC) infections.

The usual oral adult dose of azithromycin is 500 mg as a single dose daily for 3 days. Alternatively, an inital dose of 500 mg may be followed by 250 mg daily for a further 4 days.
For Uncomplicated genital infections caused by Chlamydia trachomatis and for chancroid, 1 g of azithromycin is given as a single dose. A single dose of 2 g has been given for uncomplicated gonorrhea.
For the treatment of granuloma inguinale, an initial dose of 1 g followed by 500 mg daily may be given, or 1 g may be given once a week for at least 3 weeks until all lesions have completely healed.
For prophylaxis of disseminated MAC infections, azithromycin 1.2 g may be given once weekly. For treatment or secondary prophylaxis, 500 mg once daily should be given with other antimycobacterials.
For mild or moderate typhoid caused by multidrug resistant trains, 500 mg once daily may be given for 7 days.
Administration in children: Azithromycin is licensed to use in infants and children and the usual oral dose in those over 6 months of age is 10 mg/kg once daily for 3 days, or an initial dose of 10 mg/kg may be followed by 5 mg/kg daily for a further 4 days, those who weigh over 45 kg may be given the usual adult dose. A single dose of 30 mg/kg may also be given for acute otitis media. For pharyngitis or tonsillitis in children aged over 2 years, 12 mg/kg once daily for 5 days may be given.
For prophylaxis of disseminated Mycobacterium avium complex infections, azithromycin 20 mg/kg (to a maximum of 1.2 g) once weekly or 5 mg/kg (to a maximum of 250 mg once daily may be given.
For treatment, 10 to 12 mg/kg (to a maximum of 500 mg) once daily should be given with other antimycobacterials.
The BNFC suggests that azithromycin may be used in penicillin allergic children for the prevention of secondary cases of group A streptococcal infection, those 6 months and older may be given an oral dose of 12 mg/kg (to a maximum of 500 mg) once daily for 5 days. For the treatment of mild to moderate typhoid caused by multidrug-resistant strains in those aged 6 months and over, azithromycin 10 mg/kg once daily for 7 days.

Azithromycin is contraindicated in patients with known hypersensitivity to Azithromycin, erythromycin, any macrolide or ketolide antibiotic. Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of Azithromycin.

Hypersensitivity: Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is unknown at present. 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: 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.
Treatment of pneumonia: In the treatment of pneumonia, azithromycin has only been shown to be safe and effective in the treatment of community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumonia in patients appropriate for oral therapy. Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, 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).
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.

General: Because Azithromycin is principally eliminated via the liver, caution should be exercised when Azithromycin is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing azithromycin 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.
Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Information for patients: Azithromycin tablets can be taken with or without food. Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and Azithromycin simultaneously. The patient should be directed to discontinue Azithromycin immediately and contact a physician if any signs of an allergic reaction occur. Patients should be counseled that antibacterial drugs including azithromycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Azithromycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Azithromycin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes, after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months ater having taken the last dose of the antibiotic. If this occurs, patients should contact their physicians soon as possible.
Use in Children: Acute Otitis Media (total dosage regimen: 30 mg/kg): Safety and effectiveness in the treatment of pediatric patients with otitis media under 6 months of age have not been established.
Acute Bacterial Sinusitis (dosage regimen: 10 mg/kg on Days 1-2): Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established. Use of azithromycin for the treatment of acute bacterial sinusitis in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adults and pediatric patients, and studies of acute otitis media in pediatric patients.
Community-Acquired Pneumonia (dosage regimen: 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5): Safety and effectiveness in the treatment of pediatric patients with community-acquired pneumonia under 6 months of age have not been established. Safety and effectiveness for pneumonia due to Chlamydia pneumoniae and Mycoplasma pneumoniae were documented in pediatric clinical trials. Safety and effectiveness for pneumonia due to Haemophilus influenzae and Streptococcus pneumoniae were not documented bacteriologically in the pediatric clinical trial due to difficulty in obtaining specimens. Use of azithromycin for these two microorganisms is supported, however, by evidence from adequate and well-controlled studies in adults.
Pharyngitis/Tonsillitis (dosage regimen: 12 mg/kg on Days 1-5): Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under 2 years of age have not been established.
Use in Elderly: Pharmacokinetic parameters in older volunteers (65-85 years old) were similar to those in younger volunteers (18-40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen.
In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Azithromycin 250 mg tablets contain 0.9 mg of sodium per tablet.
Azithromycin 500 mg tablets contain 1.8 mg of sodium per tablet.

Nursing Mothers: It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.

In clinical trials, most of the reported adverse effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious adverse effects of angioedema and cholestatic jaundice were reported rarely. Approximately 0.7% of the patients (adults and pediatric patients) from the 5-day multiple-dose clinical trials discontinued Azithromycin therapy because of treatment-related adverse effects. In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related adverse effects was 0.6%. In clinical trials in pediatric patients given 30 mg/kg, either as a single dose or over 3 days, discontinuation from the trials due to treatment-related adverse effects was approximately 1%. Most of the adverse effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain.
Adults: Multiple-dose regimen: Overall, the most common treatment-related adverse effects in adult patients receiving multiple-dose regimens of Azithromycin were related to the gastrointestinal system with diarrhea/loose stools (4-5%), nausea (3%) and abdominal pain (2-3%) being the most frequently reported.
No other treatment-related adverse effects occurred in patients on the multiple-dose regimens of Azithromycin with a frequency greater than 1%. Adverse effects that occurred with a frequency of 1% or less included the following: Cardiovascular: Palpitations, chest pain.
Gastrointestinal: Dyspepsia, flatulence, vomiting, melena and cholestatic jaundice.
Genitourinary: Monilia, vaginitis and nephritis.
Nervous System: Dizziness, headache, vertigo and somnolence.
General: Fatigue.
Allergic: Rash, pruritus, photosensitivity and angioedema.
Single 1-gram dose regimen: Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Adverse effects that occurred in patients on the single one-gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%) and vaginitis (1%).
Single 2-gram dose regimen: Overall, the most common adverse effects in patients receiving a single 2-gram dose of azithromycin were related to the gastrointestinal system. Adverse effects that occurred in patients in this study with a frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%) and dizziness (1%). The majority of these complaints were mild in nature.
Pediatric Patients: Single and Multiple-dose regimens: The types of side effects in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients.
Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. Side effects that occurred with a frequency of 1% or less included the following: Cardiovascular: Chest pain.
Gastrointestinal: Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis.
Hematologic and Lymphatic: Anemia and leukopenia.
Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness and insomnia.
General: Fever, face edema, fatigue, fungal infection, malaise and pain.
Allergic: Rash and allergic reaction.
Respiratory: Cough increased, pharyngitis, pleural effusion and rhinitis.
Skin and Appendages: Eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash.
Special Senses: Conjunctivitis.

Co-administration of nelfinavir at steady-state with a single oral dose of Azithromycin resulted in increased Azithromycin serum concentrations. Although a dose adjustment of Azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of Azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted.
Although, in a study of 22 healthy men, a 5-day course of Azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest that concomitant administration of Azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while the patients are receiving Azithromycin and oral anticoagulants concomitantly. Drug interaction studies were performed with Azithromycin and other drugs likely to be coadministered. When used in therapeutic doses, Azithromycin has a modest effect on the pharmacokinetics of Atorvastatin, Carbamazepine, Cetirizine, Didanosine, Efavirenz, Fluconazole, Indinavir, Midazolam, Rifabutin, Sildenafil, Theophylline (intravenous and oral), Triazolam, Trimethoprim/Sulfamethoxazole or Zidovudine. Co-administration with Efavirenz, or Fluconazole had a modest effect on the pharmacokinetics of Azithromycin. No dosage adjustment of either drug is recommended when Azithromycin is coadministered with any of the above agents. Interactions with the drugs listed as follows have not been reported in clinical trials with Azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patient is advised: Digoxin-elevated digoxin concentrations.
Ergotamine or dihydroergotamine-acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Terfenadine, cyclosporine, hexobarbital and phenytoin concentrations.

Store at temperatures not exceeding 30°C.

Macrolides

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

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