MYZID (AZITHROMYCIN) Product Data Sheet

Introduction

Table of Contents:
Introduction History FDA Approval Uses Pros and Cons Microbiology Pharmacokinetics Indication Dosage Administration Contraindication & Precaution Side Effects Drug Interaction Pregnancy & Lactation Overdose Pharmaceutical Precaution Post Marketing Experiences References

Azithromycin is a semi-synthetic macrolide antibiotic of the azalide class. Azithromycin is derived from erythromycin by adding a nitrogen atom into the lactone ring of Erythromycin. Like other macrolide antibiotics, Azithromycin inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit of the bacterial 70S ribosome. Binding inhibits peptidyl transferase activity and interferes with amino acid translocation during the process of translation. Its effects may be bacteriostatic or bactericidal depending of the organism and the drug concentration. Its long half life, which enables once daily dosing and shorter administration durations, is a property distinct from other Macrolides.

History
Since the 1970s, PLIVA's (Croatian pharmaceutical company) research team, led by Dr Slobodan Dokic, had been working in the area of macrolide antibiotics. In 1981, his team of researchers synthesized a novel antibiotic named Azithromycin. It was patented in 1981. In 1986 Pliva and Pfizer signed a licensing agreement which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva brought their azithromycin on the
market in Central and Eastern Europe under the brand name of Sumamed in 1988, and Pfizer under the brand name Zithromax in 1991. From its early trials, it

proved to be an extremely efficient antibiotic with expanded and enhanced antibacterial activity (particularly against gram-negative pathogens), prolonged and higher tissue concentration and a low incidence of gastrointestinal side effects compared to other similar antibiotics.

MYZID (AZITHROMYCIN) Product Data Sheet

FDA approved uses

Azithromycin is indicated for the treatment of the following infections due to susceptible strains of sensitive organisms:

Upper respiratory tract infections: pharyngitis/tonsillitis, sinusitis, otitis media Lower respiratory tract infections: bronchitis, acute exacerbation of chronic bronchitis, community acquired pneumonia of mild severity. Sexually transmitted diseases: uncomplicated urethritis, uncomplicated cervicitis due to Neisseria gonorrhoeae or Chlamydia trachomatis. Chancroid (genital ulcer disease in men). Skin and soft tissue infections: erysipelas, impetigo, secondary pyoderma, erythema migrans. Mycobacterial Infections.

Infectious diseases:

Pelvic inflammatory disease (PID)

PID comprises a spectrum of inflammatory disorders of the upper female genital tract, including any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis. Sexually transmitted organisms, Neisseria gonorrhoeae and Chlamydia trachomatis are the major pathogens causing PID. Azithromycin provides a short simple treatment option for PID 3.

Infectious diarrhoea

Infectious diarrhoea is the most common cause of diarrhoea worldwide. Azithromycin is a good choice for pregnant women and children, for whom Fluoroquinolones are not approved, and for patients who cannot otherwise tolerate Fluoroquinolones 4.

Dental infections

Azithromycin is given to people allergic to penicillins and those who have abscesses and other dental infections, especially those extending into the sinuses, gums and bone, and for whom other antibiotics have proved ineffective.

Acne

Acne vulgaris is a common inflammatory disorder of the skin. Azithromycin is a safe and effective alternative in the treatment of inflammatory acne with few side effects and good compliance, even in adolescents. In 2004, researchers studied azithromycin in patients with moderate to severe papulopustular acne vulgaris 6. The researchers found that 83% of patients showed at least a 60% improvement in only 4 weeks and the majority achieved 80% clearance in 12 weeks.

MYZID (AZITHROMYCIN) Product Data Sheet

Pertussis Azithromycin is as effective as and better tolerated than erythromycin for the treatment of pertussis7. Prostatitis Azithromycin is used in the treatment of chronic prostatitis caused by Chlamydia trachomatis and Neisseria gonorrhoeae. Syphilis Azithromycin has been successfully used as a multidose treatment in persons who have early syphilis8.

Non-infectious diseases:

Atherosclerosis Azithromycin appears to reduce the risk of Chlamydia pneumoniae-induced atherosclerosis11. Cystic fibrosis

According to the studies2, azithromycin significantly improves quality of life, reduces the number of respiratory exacerbations, and reduces the rate of decline in lung function in persons with cystic fibrosis. While the exact mechanisms are unknown, anti-inflammatory rather than antimicrobial properties of Macrolides seem to be responsible for the beneficial effects.

Azithromycin "pros" and "cons"

Advantages:

Excellent efficacy. Many scientific studies have shown that azithromycin is better or equally effective compared to other antibiotics. Low potential for drug interactions. Azithromycin, unlike the majority of Macrolides, does not bind to cytochrome P-450 in the liver, resulting in low potential for drug to drug interaction. Low rate of side effects. Side effects with azithromycin are mild to moderate, mostly gastrointestinal. Sustained antimicrobial activity. Azithromycin reaches high and sustained tissue concentrations that results in sustained antimicrobial activity. Active against intracellular bacteria (Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella spp.). Since azithromycin is a weak base, it easily penetrates the cell membrane and stays within the cell. Targeted activity at the site of infection. Because of the transport with white blood cells, azithromycin possesses a unique property - targeted activity at the site of infection. In infected tissues, azithromycin achieves high and sustained therapeutic concentrations that last five to seven days after the last dose. Suitable choice for empirical therapy. Since azithromycin has a good activity against the most common pathogens it is used as a choice for empirical therapy. Good compliance: short once daily dosing regimen. Azithromycin short dosing regimen is convenient and improves patient compliance. For the majority of

MYZID (AZITHROMYCIN) Product Data Sheet infections, azithromycin is administered once daily for three days. In the treatment of sexually transmitted diseases, azithromycin is administered as a single dose. Active against most respiratory tract infections. Betalactams lack activity against atypical pathogens. Among macrolides, azithromycin shows the best activity against H. influenzae. Erythromycin April 09, 1959 Yes Yes 1-1.5 hours 25% High
B

Generic name FDA approval date Intravenous form Fed state affects absorption Half-life Bioavailability Potential for interactions
FDA Pregnancy Category

Clarithromycin October 31, 1991 No No 3-7 hours 55% High

C

Azithromycin November 1, 1991 Yes No 40-60 hours 38% Low

B

Microbiology
Azithromycin demonstrates activity in vitro against a wide range of bacteria including the following:

Gram-positive aerobic bacteria - Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic streptococci), Streptococcus pneumoniae, alpha-haemolytic streptococci and other streptococci, and Corynebacterium diphtheriae. Azithromycin demonstrates cross resistance with erythromycin resistant-positive strains, including Streptococcus faecalis (enterococcus) and most strains of methicillin-resistant staphylococci. Gram-negative aerobic bacteria - Haemophilus influenzae (including betalactamase producing Haemophilus influenzae), Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter species, Yersinia species, Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella species, Pasteurella species, Vibrio cholerae and parahaemolyticus, Plesiomonas shigelloides. Activities against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter species, Aeromonas hydrophila and Klebsiella species are variable and susceptibility tests should be performed. Anaerobic bacteria - Bacteroides fragilis and Bacteroidesspecies, Clostridium perfringens, Peptococcus species, Peptostreptococcus species, Fusobacterium necrophorum and Propionibacterium acnes. Sexually Transmitted Diseases - azithromycin is active against Chlamydia trachomatis and also shows good activity against Treponema pallidum, Neisseria gonorrhoeae and Haemophilus ducreyi. Other Organisms - Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Campylobacter species and Listeria monocytogenes. Opportunistic pathogens associated with (HIV) infections - Mycobacterium avium-intracellulare complex.

MYZID (AZITHROMYCIN) Product Data Sheet Azithromycin demonstrates activity in vivo against the following bacteria: Gram-positive aerobic bacteria - Staphylococcus aureus, Streptococcus pyogenes (group A beta-haemolytic streptococci), Streptococcus pneumoniae, alphahaemolytic streptococci (viridans group) and other streptococci. Gram-negative aerobic bacteria - Haemophilus influenzae (including betalactamase producing Haemophilus influenzae), Haemophilus parainfluenzae, Moraxella catarrhalis. Other organisms - Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumoniae. Opportunistic pathogens associated with HIV infections - Mycobacterium avium-intracellulare complex.

Pharmacokinetics
Absorption Azithromycin is acid-stable, so can be taken orally with no need of protection from gastric acids. It is readily absorbed, but its absorption is greater on an empty stomach. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and one to two hours after a dose. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. Following oral administration of a single 500 mg dose to fasted subjects, mean maximum serum concentration (Cmax) of 0.24 to 0.87 g/mL was achieved in about 1.0 to 3.5 hours, with a mean area under the curve (AUC0-24) of 3.05 g.hr/mL. The absolute bioavailability of azithromycin is 37% following oral administration. Distribution Azithromycin is distributed widely throughout the body. Rapid movement of azithromycin from blood into tissues results in significantly higher azithromycin concentrations in tissue than in plasma. It appears to be concentrated intracellularly. Concentrations in tissues, e.g. lung, tonsil and prostate, exceed the MIC90 for likely pathogens after a single dose of 500 mg, and remain high after serum or plasma concentrations decline to below detectable levels. Azithromycin is highly concentrated in phagocytes and fibroblasts. Phagocytes transport the drug to the site of infection and inflammation. Volume of distribution -31.1 L/kg Protein binding: Serum protein binding is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 g/mL to 7% at 2 g/mL. Metabolism: Hepatic. Approximately 35% metabolized by demethylation. Up to 10 metabolites, which are thought to have no significant antimicrobial activity, may be found in the bile. In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Route of elimination: Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over 50% of the dose is eliminated through biliary excretion as unchanged drug. For oral dosage forms, approximately 4.5% of the dose is eliminated in the urine as unchanged drug within 72 hours. Half life: According to Davis' Drug Guide for Nurses, following a single 500 mg dose, the half-life of azithromycin is 1114 hours. The longer half-life of 68 hours is achieved only when multiple doses are consumed. Clearance : Apparent plasma Cl=630 mL/min [following single 500 mg oral and IV doses] Toxicity: Potentially serious side effects of angioedema and cholestatic jaundice were reported.

MYZID (AZITHROMYCIN) Product Data Sheet

Indications:
Azithromycin is indicated for use in adults for the treatment of the following infections of mild to moderate severity: 1. Lower respiratory tract infections Acute bacterial bronchitis due to Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis Community-acquired pneumonia due to Streptococcus pneumoniae Haemophilus influenzae in patients suitable for outpatient oral treatment Community-acquired pneumonia caused patients who require initial intravenous therapy. by susceptible organisms or in

In clinical studies, efficacy has been demonstrated against Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophilia, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae. 2. Upper respiratory tract infections Acute sinusitis due to Streptococcus pneumoniae or Haemophilus influenzae Acute streptococcal pharyngitis Note: penicillin is the usual drug of choice in the treatment of Streptococcus pyrogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin appears to be almost as effective in the treatment of streptococcal pharyngitis. Acute otitis media 3. Uncomplicated skin and skin structure infections Uncomplicated infections due to Staphylococcus aureus, Streptococcus pyogenes or Streptococcus agalactiae Surgical drainage is usually required for abscesses. 4. Sexually transmitted diseases Uncomplicated urethritis and cervicitis due to Chlamydia trachomatis or non multi-resistant Neisseria gonorrhoeae Note: at the recommended dose, Azithromycin cannot be relied upon to treat syphilis. As with other drugs for the treatment of non-gonococcal infections, azithromycin may mask or delay the symptoms of incubating syphilis and, therefore, concurrent infection with Treponema pallidum should be excluded. Appropriate tests should be performed for the detection of syphilis and treatment should be instituted as required. 5. Pelvic inflammatory disease caused by susceptible organisms (Chlamydia trachomatis, Neisseria gonorrhoea, Mycoplasma hominis), in patients who require initial intravenous therapy

MYZID (AZITHROMYCIN) Product Data Sheet 6. Chlamydia trachomatis conjunctivitis and Trachoma 7. Prevention of infection due to Mycobacterium avium-intracellulare complex disease, when used as the sole agent or in combination with rifabutin at its approved dose, in adults with HIV infection and CD4 cell count less than or equal to 75 cells/L.

Indication :
Acute Otitis Media (AOM) caused by H. influenzae, M. catarrhalis, or S. pneumoniae. Pharyngitis and Tonsillitis caused by susceptible Streptococcus pyogenes Symptomatic enteric infections caused by Campylobacter jejuni Shigellosis caused by susceptible strains of Shigella dysenteriae, S. boydii, S. flexneri, or S. sonnei Treatment of travelers diarrhea Acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) caused by H. influenzae, M. catarrhalis, or S. pneumoniae. Mild to moderate Community-acquired pneumonia (CAP) caused by susceptible S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, or Chlamydophila pneumonia Uncomplicated skin and skin structure infections caused by susceptible S. aureus, S. pyogenes, or S. agalactiae Babesiosis caused by Babesia microti. Treatment of chancroid (genital ulcers caused by Haemophilus ducreyi). Chlamydial Infections (uncomplicated urethritis or cervicitis caused by C. trachomatis.) Gonorrhea (Treatment of uncomplicated urethritis or cervicitis caused by susceptible Neisseria gonorrhoeae.) Mycobacterium avium Complex (MAC) Infections Pelvic Inflammatory Disease (Treatment of acute pelvic inflammatory disease (PID) caused by C. trachomatis, Mycoplasma hominis, or N. gonorrhoeae) Pertussis Treatment of pertussis caused by Bordetella pertussis Toxoplasmosis Treatment of infections caused by Toxoplasma gondii, including toxoplasmic encephalitis in HIV-infected patients Syphilis

Dosage and Administration

Children over 6 months of age is 10 mg/kg body weight once daily for 3 days or 10 mg/kg on day 1, followed by 5 mg/kg for next 4 days is also recommended. Body Weight (Age) 15-25 kg (3-7 years) 26-35 kg (8-11 years) 36-45 kg (12-14 years) Over 45kg Dose 200mg once daily 300mg once daily 400mg once daily Duration 3 days 3 days 3 days

Normal adult dosage is recommended

MYZID (AZITHROMYCIN) Product Data Sheet Azithromycin is administered as a single daily dose, taken with or without food. Infections Upper & Lower Respiratory Tract Infections Chancroid (Genital Ulcer Disease) Non-gonococcal urethritis and cervicitis Gonococcal urethritis and cervicitis Typhoid Fever Shigellosis Cholera Recommended (Adult) dose & duration of therapy 500mg as a single dose for 3 days or 500mg once on day 1, followed by 250mg once daily for next 4 days. 1g as a single dose 1g as a single dose 2g as a single dose 500mg once daily for 7 days 500mg once on day 1, followed by 250mg once daily for next 4 days 1g as a single dose

Contraindication & Precaution

Myzid (Azithromycin) is contra-indicated in patients with a known hypersensitivity to azithromycin or any of the macrolide antibiotics. Because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered. As the liver is the principal route of excretion of azithromycin it should not be used in patients with hepatic disease. Avoid concomitant administration with terfenadine or astemizole. Precaution should be taken in patients with more severe renal impairment. Renal impairment
No dose adjustment is needed in patients with mild or moderate renal impairment. After oral administration of a single dose of azithromycin 1g in subjects with severe renal impairment (GFR < 10 mL/min), mean AUC0-120 and mean Cmax were increased by approximately 30% and 60%, respectively, when compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to patients with severe renal impairment.

Hepatic impairment
No dose adjustment is recommended for patients with mild to moderate hepatic impairment (GFR 10 to 80 mL/min). Nonetheless, 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.

Side Effects:

Myzid (Azithromycin) is well tolerated with a low incidence of side-effects. The side-effects include nausea, vomiting, abdominal discomfort (pain/cramps), flatulence, diarrhoea, headache, dizziness, and skin rashes and are reversible upon discontinuation of therapy.

MYZID (AZITHROMYCIN) Product Data Sheet In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Rarely but potentially serious side effects were angioedema and cholestatic jaundice. Less serious Azithromycin side effects may include:

Mild nausea, vomiting, diarrhea, constipation; Stomach pain or upset; Dizziness, tired feeling, or headache; Nervous feeling, sleep problems (insomnia); Vaginal itching or discharge; Mild itching or skin rash; Ringing in your ears, problems with hearing; or Decreased sense of taste or smell.

Drug Interaction
Antacids, aluminum- and magnesium-containing (concurrent use with antacids decreases the peak serum concentration [C max] of azithromycin by approximately 24%, but has no effect on the area under the plasma concentrationtime curve [AUC]; oral azithromycin should be administered at least 1 hour before or 2 hours after aluminumand magnesium-containing antacids) Carbamazepine or Cyclosporine or Digoxin or Hexobarbital or Phenytoin or Terfenadine (concurrent use with macrolide antibiotics has been associated with increased serum concentrations of carbamazepine, cyclosporine, digoxin, hexobarbital, phenytoin, and terfenadine; patients concurrently receiving azithromycin and any of these medications should be monitored carefully) Dihydroergotamine or Ergotamine (concurrent use with macrolide antibiotics has been associated with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia; patients concurrently receiving azithromycin and either of these medications should be monitored carefully) Theophylline (concurrent use with macrolide antibiotics has been associated with increased serum concentrations of theophylline, plasma concentrations of theophylline should be monitored in patients concurrently receiving azithromycin and theophylline) Triazolam (concurrent use with macrolide antibiotics has been associated with a decrease in the clearance of triazolam, which may increase its effects; patients concurrently receiving azithromycin and triazolam should be monitored carefully) Warfarin (concurrent use with macrolide antibiotics has been associated with increased anticoagulant effects; prothrombin time should be monitored carefully in patients concurrently receiving azithromycin and warfarin)

MYZID (AZITHROMYCIN) Product Data Sheet

Pregnancy and Lactation

US FDA Pregnancy Category B. In recent clinical studies have recommended that azithromycin should be considered for the initial treatment of chlamydial cervicitis in pregnancy. In other infections, azithromycin should be used only when clearly needed. It is not known whether azithromycin is excreted in breast milk. Exercise caution when administering to a nursing women.

Overdose

There are no data on over dosage with azithromycin. Typical symptoms of over dosage with macrolide antibiotics include hearing loss, severe nausea, vomiting and diarrhoea. Gastric lavage and general supportive measures are indicated.

Pharmaceutical Precautions
Shelf-life: 36 months Storage: Store in a cool, dry place where it stays below 25C

Post-Marketing Experience:
Adverse events reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria, angioedema. Cardiovascular: Arrhythmias including ventricular tachycardia, hypotension. There have been rare reports of QT prolongation and torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration. General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal). Genitourinary: Interstitial nephritis and acute renal failure, vaginitis. Hematopoietic: Thrombocytopenia. Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death. Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Psychiatric: Aggressive reaction and anxiety. Skin/Appendages: Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome, and toxic epidermal necrolysis. Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, reports of taste/smell perversion and/or loss.

MYZID (AZITHROMYCIN) Product Data Sheet References 1. SUMAMED - success story, from sumamed.com.hr 2. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax. 2002 Mar;57(3):212-6. 3. Bevan CD, Ridgway GL, Rothermel CD. Efficacy and safety of azithromycin compared with two standard multidrug regimens for the treatment of acute pelvic inflammatory disease. J Int Med Res. 2003 Jan-Feb;31(1):45-54. PubMed 4. Reveneau N, Crane DD, Fischer E, Caldwell HD. Bactericidal activity of first-choice antibiotics against gamma interferon-induced persistent infection of human epithelial cells by Chlamydia trachomatis. Antimicrob Agents Chemother. 2005 May;49(5):1787-93. 5. Khan WA, Seas C, Dhar U, Salam MA, Bennish ML. Treatment of shigellosis. Ann Intern Med. 1997 May 1;126(9):697-703. PubMed 6. Kapadia N, Talib A. Acne treated successfully with azithromycin. Int J Dermatol. 2004 Oct;43(10):766-7. PubMed 7. Langley JM, Halperin SA, Boucher FD, Smith B; Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC). Azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis. Pediatrics. 2004 Jul;114(1):e96-101. 8.Gruber F, Kastelan M, Cabrijan L, Simoni E, Brajac I. Treatment of early syphilis with azithromycin. J Chemother. 2000 Jun;12(3):240-3. 9. Dzelalija B, Petrovec M, Avsic-Zupanc T, Strugar J, Milic' TA. Randomized trial of Zithromax in the prophylaxis of Mediterranean spotted fever. Acta Med Croatica. 2002;56(2):45-7. PubMed 10. Rouse MS, Steckelberg JM, Brandt CM, Patel R, Miro JM, Wilson WR. Efficacy of azithromycin or clarithromycin for prophylaxis of viridans group streptococcus experimental endocarditis. Antimicrob Agents Chemother. 1997 Aug;41(8):1673-6. 11. Bouwman JJ, Visseren FL, Bevers LM, van der Vlist WE, Bouter KP, Diepersloot RJ. Azithromycin reduces Chlamydia pneumoniae-induced attenuation of eNOS and cGMP production by endothelial cells. Eur J Clin Invest. 2005 Sep;35(9):573-82. PubMed