Azee Azithromycin Tablets

Azee AZITHROMYCIN TABLETS

Description, Composition, Clinical pharmacology:  Pharmacodynamics, Pharmacokinetics; Indications, Contraindications, Warnings, Precautions: Effects on ability to drive, Usage in pregnancy and lactation, Usage in paediatrics, Usage in geriatrics, Drug interactions, Laboratory test interactions; Adverse reactions, Overdosage, Dosage and administration, Storage, Presentation and Maker of Azee Tablet Medicine for Infections.

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory.

 

DESCRIPTION

Azithromycin is an azalide, derived from the macrolide class of antibiotics.
It 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-hexo pyranosyl] oxy]-1-oxa-6- azacyclopentadecan-15-one. Its molecular formula is C38H72N2O12 and its molecular weight is 749.00.

Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl- substituted nitrogen atom is incorporated into the lactone ring.

 

COMPOSITION

Azee-250

Each film-coated tablet contains:

Azithromycin USP (As Dihydrate)

equivalent to Anhydrous Azithromycin 250 mg

 

Azee-500

Each film-coated tablet contains:

Azithromycin USP (As Dihydrate)

equivalent to Anhydrous Azithromycin 500 mg

 

CLINICAL PHARMACOLOGY

Pharmacodynamics

Azithromycin acts by binding to the 5OS ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected. Azithromycin concentrates in phagocytes and fibroblasts. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Azithromycin usually is bacteriostatic, although the drug may be bactericidal in high concentrations against selected organisms. Bactericidal activity has been observed in vitro against Streptococcus pyogenes, S. pneumoniae and Haemophilus influenzae.

 

Microbiology

Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

 

Aerobic and facultative gram-positive microorganisms

Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae and Streptococcus pyogenes.

 

Aerobic and facultative gram-negative microorganisms

Haemophilus ducreyi, Haemophilus influenzae, Moraxella catarrhalis and Neisseria gonorrhoeae.

 

Other microorganisms

Chlamydia pneumoniae, Chlamydia trachomatis and Mycoplasma pneumoniae.
Beta-lactamase production should have no effect on azithromycin activity.

The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin.

However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

 

Aerobic and facultative gram-positive microorganisms

Streptococci (Groups C, F, G) and Viridans group streptococci.

 

Aerobic and facultative gram-negative microorganisms

Bordetella pertussis and Legionella pneumophila.

 

Anaerobic microorganisms

Peptostreptococcus species and Prevotella bivia.

 

Other microorganisms

Ureaplasma urealyticum.

 

Pharmacokinetics

Azithromycin is rapidly absorbed from the gastrointestinal tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. Following oral administration in humans, bioavailability is approximately 37%. Food was shown to increase Cmax but had no effect on AUC.

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/ml to 7% at 2 µg/ml.

Following oral administration, azithromycin is widely distributed throughout the body. Greater azithromycin concentrations in tissues than in plasma or serum were observed. The antimicrobial activity of azithromycin is pH related and appears to be reduced with decreasing pH. Very low concentrations were noted in cerebrospinal fluid (less than 0.01 µg/mL) in the presence of non-inflamed meninges.

Plasma concentrations of azithromycin following single 500 mg oral doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 ml/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

 

Special Populations

Renal insufficiency

Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mI/min) compared to subjects with normal renal function (GFR >80 mI/min). The mean Cmax, and AUC0-120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR <10 mI/min) compared to subjects with normal renal function (GFR >80 mI/min).

 

Hepatic insufficiency

The pharmacokinetics of azithromycmn in subjects with hepatic impairment have not been established.

 

Geriatric patients

The pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

 

INDICATIONS

Azithromycin is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the microorganisms in the specific conditions listed below.

 

Adults:

• Acute bacterial exacerbations of chronic obstructive pulmonary disease.

• Acute bacterial sinusitis.

• Community-acquired pneumonia.

• Pharyngitis/tonsillitis as an alternative to first-line therapy in individuals who cannot use first-line therapy.

• Uncomplicated skin and skin structure infections – Abscesses usually require surgical drainage.

• Urethritis and cervicitis

• Genital ulcer disease in men due to chancroid. Due to the small number of women included in clinical trials, the efficacy of azithromycmn in the treatment of chancroid in women has not been established.

Azithromycmn, at the recommended dose, should not be relied upon to treat syphilis.

• Prophylaxis of disseminated Mycobacterium avium complex (MAC) disease – Azithromycin taken alone or in combination with rifabutin at its approved dose is indicated for the prevention of disseminated MAC disease in people with advanced HIV infection.

• Treatment of disseminated MAC disease – Azithromycmn taken in combination with ethambutol is indicated for the treatment of disseminated MAC infections in people with advanced HIV infection.

 

Paediatric patients:

• Acute otitis media.

• Community-acquired pneumonia’ in patients appropriate for oral therapy.

• Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.

Azithromycmn 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,

– Patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia) or

– Elderly or debilitated patients.

 

Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycmn. Therapy with azithromycmn may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

 

CONTRAINDICATIONS

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide antibiotic. Because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be coadministered.

 

WARNINGS

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.

In the treatment of pneumonia, azithromycmn 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 pneumoniae in patients appropriate for oral therapy. Azithromycmn 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).

Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration ofantibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis.” After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

 

PRECAUTIONS

General

Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycmn 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 azithromycmn 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.

Prescribing azithromycmn 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.

 

Effect on ability to drive and use machines

There is no evidence to suggest that azithromycin may have an effect on a patient’s abilityto drive or operate machinery.

 

Usage in pregnancy and lactation

There are 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.

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.

 

Usage inpaediatrics

Safety and effectiveness in the treatment of paediatric patients with otitis media, acute bacterial sinusitis and community acquired pneumonia under 6 months of age have not been established.

Safety and effectiveness in the treatment of paediatric patients with pharyngitis/ tonsillitis under 2 years of age have notbeen established.

Studies evaluating the use of repeated courses of therapy have not been conducted.
Safety and efficacy of oral azithromycin for the treatment or prevention of Mycobacterium avium complex (MAC) infection in children with human immunodeficiency virus (HIV) infection have notbeen established.

 

Usage in geriatrics

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. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen.

 

Drug interactions

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.

Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.

Azithromycin had no significant effect on the pharmacokinetics of methyl prednisolone.
When used in therapeutic doses, azithromycin had 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. Coadministration 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 below 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 patients 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.

The AUC of azithromycin was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the Cmax was reduced by 24%. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid. Administration of cimetidine two hours prior to azithromycin had no effect on azithromycin absorption. Macrolide antibiotics may inhibit metabolism of pimozide, resulting in increased plasma concentrations of unchanged drug. Because such alterations in pharmacokinetics of pimozide may be associated with prolongation of the QT and QTc interval, concomitant administration of pimozide and azithromycin is contraindicated.

 

Laboratory test interactions

There are no reported laboratory test interactions.

 

ADVERSE REACTIONS

Most of the reported side effects of azithromycin were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious side effects of angioedema and cholestatic jaundice were reported rarely. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain.

 

Adults:

Multiple-dose regimens: Overall, the most common treatment-related side 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.

Side 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: Side 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: Side effects that occurred in patients 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.

 

Paediatric patients

The types of side effects in paediatric patients were comparable to those seen in adults. The most frequent side effects attributed to treatment were diarrhea, abdominal pain, vomiting, nausea, headache 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.

 

Laboratory Abnormalities

Adults

Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, neutrophils and blood glucose; elevated serum creatine phosphokinase, potassium, ALT, GGT, AST, BUN, creatinine, blood glucose, platelet count, lymphocytes, neutrophils and eosinophils; with an incidence of less than 1%: leukopenia, neutropenia, decreased sodium, potassium, platelet count, elevated monocytes, basophils, bicarbonate, serum alkaline phosphatase, bilirubin, LDH and phosphate. The majority of subjects with elevated serum creatinine also had abnormal values at baseline.

When follow-up was provided, changes in laboratory tests appeared to be reversible.

 

Paediatric patients

One, three and five day regimens

Laboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over 5 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring atincidences of 1- 5%. An absolute neutrophil count between 500-1500 cells/mm3 was observed in 10/64 patients receiving 30 mg/kg as a single dose, 9/62 patients receiving 30 mg/kg given over 3 days, and 8/63 comparator patients. No patient had an absolute neutrophil count <500 cells/mm3.

In multiple-dose clinical trials, no patients discontinued therapy because of treatment-related laboratory abnormalities.

 

OVERDOSAGE

There are no data available on overdosage with azithromycin. Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. Typical symptoms of overdosage with macrolide antibiotics include hearing loss, severe nausea, vomiting and diarrhoea.

In the event of overdosage, gastric lavage and general symptomatic and supportive measures are indicated as required.

 

DOSAGE ANDADMINISTRATION

Adults: Azithromycin tablets can be taken with or without food.

lnfection*** Recommended dose / duration of therapy
Community-acquired
pneumonia (mild severity)
Pharyngitis/tonsillitis
(second line therapy)
Skin/skin structure
(uncomplicated)
500 mg as a single dose
on Day 1, followed by
250 mg once daily on
Days 2 through 5.
Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate) 500 mg QD x 3 days OR
500 mg as a single dose
on Day 1, followed by
250 mg once daily on Days
2 through 5.
Acute bacterial sinusitis 500 mg QD x 3 days

 

Genital ulcer disease (chancroid) One single 1 gram dose
Non-gonoccocal urethritis and cervicitis One single 1 gram dose
Gonococcal urethritis and cervicitis One single 2 gram dose

***Due to the indicated organisms

 

Prevention of disseminated MAC infections: 1200 mg taken once weekly. This dose of azithromycin may be combined with the approd dosage regimen of rifabutin.

Treatment of disseminated MAC infections: 600mg/day in combination with ethambutol at the recommended daily dose of 15mg/Kg. Other antimycobacterial drugs that have shown in vitro activity against MAC may be added to the regimen of azithromycin plus ethambutol at the discretion ofthe physician.

 

Paediatric patients

Acute otitis media: The recommended dose of azithromycin for the treatment of paediatric patients with acute otitis media is 30 mg/kg given as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on the first day followed by 5 mg/kg/day on Days 2 through 5. The safety of re-dosing azithromycin in paediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established.

Acute bacterial sinusitis: The recommended dose of azithromycin for the treatment of paediatric patients with acute bacterial sinusitis is 10 mg/kg once daily for 3 days.

Community-acquired pneumonia: The recommended dose of azithromycin for the treatment of paediatric patients with community-acquired pneumonia is 10 mg/kg as a single dose on the first day followed by 5 mg/kg on Days 2 through 5.

Pharyngitis/Tonsillitis: The recommended dose of azithromydn for children with pharyngitis/tonsillitis is 12 mg/kg once dailyfor 5 days.

 

Renal insufficiency

No dosage adjustment is recommended for subjects with renal impairment (GFR ≤ 80 ml/min). The mean AUC0-120 was similar in subjects with GFR 10-80 ml/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 ml/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment.

 

Hepatic insufficiency

As the liver is the principal route of excretion of azithromycin, it should not be used in patients with hepatic disease.

 

STORAGE

Store below 25oC, in a dry place.

 

PRESENTATION

Azee-250 : Strip of 6 tablets.

Azee-500 : Strip of 3 tablets.

Keep outof reach of children.

 

Made in India by

lpca Laboratories Ltd.

Regd. Off.: 48, Kandivli Ind. Estate, Mumbai 400 067