ZITROMAX Suspension

For infections caused by susceptible organisms; in lower respiratory tract infections including bronchitis and pneumonia, in odontostomatological infections, 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 for the treatment of uncomplicated genital infections due to Chlamydia trachomatis.

It is also indicated for the treatment of chancroid due to Haemophilus ducreyi and uncomplicated genital infections due to non-multiresistant 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 infections due to non-multiresistant Neisseria gonorrhoeae, concurrent 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.

Posology and Method of Administration

Oral azithromycin should be administered as a single daily dose. The period of dosing with regard to infection is given below.

This medicine can be taken with or without food.

In adults

For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis and Haemophilus ducreyi, the dose is 1000mg as a single oral dose.

For susceptible Neisseria gonorrhoeae the recommended dose is 1000mg or 2000mg of azithromycin in combination with 250mg or 500mg 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 the HIV, the dose is 1200mg once/week.

For the treatment of DMAC infections in patients with advanced HIV infection, the recommended dose is 600mg 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 all other indications in which the oral formulation is administered, the total dosage of 1500mg should be given as 500mg daily for 3 days. As an alternative, the same total dose can be given over 5 days with 500mg given on Day 1, then 250mg daily on Days 2-5.

In children

The maximum recommended total dose for any treatment is 1500mg for children.

In general, the total dose in children is 30mg/kg. Treatment for pediatric streptococcal pharyngitis should be dosed at a different regimen.

The total dose of 30mg/kg should be given as a single daily dose of 10mg/kg daily for 3 days, or given over 5 days with a single daily dose of 10mg/kg on Day 1, then 5mg/kg on Days 2-5.

As an alternative to the above dosing, treatment for children with acute otitis media can be given as a single dose of 30mg/kg.

For pediatric streptococcal pharyngitis, azithromycin given as a single dose of 10mg/kg or 20mg/kg for 3 days has been shown to be effective; however, a daily dose of 500mg 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 20mg/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 15kg, azithromycin suspension should be measured as closely as possible. For children weighing 15mg or more, azithromycin suspension should be administered according to the guide provided below.: See the package insert.

Azithromycin tablets should only be administered to children weighing more than 45kg.

See the package insert about the details below:

- In the Elderly

- In patients with renal impairment

- In patients with hepatic impairment.

The use of this product is contraindicated in patients with a hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any excipient.

See the package insert about the details below:

- Blood and lymphatic system disorders: Transient episodes of mild neutropenia

- Ear and Labyrinth Disorders: hearing impairment (including hearing loss, deafness and/or tinnitus)

- Gastrointestinal Disorders: Nausea, vomiting, diarrhoea loose stools, abdominal discomfort (pain/cramps), and flatulence.

- Hepatobiliary Disorders: Abdominal 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 adverse reactions in HIV-infected patients receiving azithromycin for prophylaxis for DMAC were diarrhoea, abdominal pain, nausea, loose stools, flatulence, vomiting, dyspepsia, rash, pruritus, headache, and arthralgia.

When 600mg azithromycin 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, diarrhoea, flatulence, headache, abdominal 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)

- Metabolism and Nutrition Disorders: Anorexia

- Psychiatric Disorders: Aggressive reaction nervousness, agitation, ad 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 ad arrhythmias including ventricular tachycardia have been reported. There have been rare reports of QT prolongations and torsades de pointes.

- Vascular Disorders: Hypotension

- Gastrointestinal disorders: Vomiting/diarrhea (rarely resulting in dehydration), dyspepsia, constipation ,pseudomembranous colitis, pancreatitis, ad 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.

- Skin and Subcutaneous Tissue Disorders: Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria, and angioedema. Rarely, serious cutaneous adverse reactions including erythema multiforme, 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.

See the package insert about the details below:

- Antacids

- Cetirizine

- Didanosine (Dideoxyinosine)

- Digoxin

- Ergot

- Zidovudine

- Atorvastatin

- Carbamazepine

- Cimetidine

- Coumarin-type oral anticoagulants

- Cyclosporin

- Efavirenz

- Fluconazole

- Indinavir

- Methylprednisolone

- Midazolam

- Nelfinavir

- Rifabutin

- Sildenafil

- Terfenadine

- Theophylline

- Triazolam

- Trimethoprim/sulfamethoxazole

Pregnancy

Azithromycin should be used during pregnancy only if clearly needed. (See the package insert about the details.)

Lactation

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.

See the package insert about the details below:

- Hypersensitivity

- Hepatotoxicity

- Infantile hypertrophic pyloric stenosis

- Ergot derivatives

- Superinfection: As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.

- Clostridium difficile-associated diarrhea

- Renal impairment

- Diabetes

- Prolongation of the QT interval

- Myasthenia gravis

Pharmacotherapeutic group: Macrolides

Azithromycin is the first of a subclass of macrolide antibiotics, known as azalides, and is chemically different from erythromycin. Chemically it is derived by insertion of a nitrogen atom into the lactone ring of erythromycin A.

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.

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. 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 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, Streptococcus agalactiae*, Streptococcus pyogenes*, other beta-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 ad 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 jiroveci and Toxoplasma gondii.

* The efficacy of azithromycin against the indicated species has been demonstrated in clinical trials.