AZIBOSTON (sachets)

DOSAGE

Adults

The total dose of azithromycin is 1500 mg which should be given over 3 days (500 mg once daily) or 5 days (500 mg as a single dose on day 1, followed by 250 mg once daily on days 2 through 5).

In non-gonococcal urethritis and cervicitis and genital ulcer disease (chancroid), the dose is 1000 mg as a single oral dose.

In gonococcal urethritis and cervicitis, one single 2000 mg dose is recommended.

Pediatric patients

There is no safety information on children less than 6 months of age.

The recommended total dose is 30 mg/kg, which can be given as single dose (1-day regimen) or 10 mg/kg once daily for 3 days (3-days regimen) or 10 mg/kg as a single dose on the first day followed by 5 mg/kg/day on days 2 through 5 (5-days regimen).

In treatment of pharyngitis/tonsillitis, the recommended dose for children is 12 mg/kg once daily for 5 days.

An example for 3-days regimen:

Children 15 – 25 kg (3 – 7 years of age): 1 sachet, once daily for 3 days.

Children 26 – 35 kg (8 – 11 years of age): 1½  sachet, once daily for 3 days.

Children 36 – 45 kg (12 – 14 years of age): 2 sachet, once daily for 3 days.

For children over 45 kg, dose as per adults.

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).

Hepatic impairment

Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin.

ADMINISTRATION

AZIBOSTON is administered orally. Disperse the powder with a small amount of water before use. This product can be taken with or without food. It is recommeded not to take aluminium- and magnesium-containing antacids and azithromycin simultaneously.

CONTRAINDICATIONS

Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic.

Patients with a history of cholestatic jaundice/ hepatic dysfunction associated with prior use of azithromycin.

WARNINGS AND PRECAUTIONS

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.

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 (CAD) due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae 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 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 producing 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. Therefore, 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. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.

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 other macrolides, including azithromycin. Therefore caution is required when treating patients:

With congenital or documented QT prolongation

Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhythmics of Classes Ia and III, cisapride and terfenadine

With electrolyte disturbance, particularly in case of hypokalemia and hypomagnesemia

With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

Elderly patients may be more susceptible to drug-associated effects on the QT interval.

Renal impairment

In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).

Streptococcal infections

Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.

Myasthenia gravis

Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy.

Superinfection

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

Diabetes

Caution in diabetic patients: contains 1256.5 mg of saccharose.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

INTERACTIONS

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid 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.

Nelfinavir: Co-administration of azithromycin (1200 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.

Digoxin: Some of the macrolide antibiotics have been reported to impair the microbial metabolism of digoxin in the gut in some patients. In patients receiving concomitant azithromycin, a related azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.

Ergot derivatives: In patients receiving ergot derivatives, ergotism has been precipitated by 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-administrated.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Drug interactions studies were performed with azithromycin and other drugs likely to be co-administered. 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. 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.

Laboratory test interactions: There are no reported laboratory test interactions.

PREGNANCY AND LACTATION

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 foetus 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

There are no data on secretion in breast milk. As many drugs are excreted in human milk, azithromycin should not be used in the treatment of a lactating woman unless the physician feels that the potential benefits justify the potential risks to the infant.

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.

Undesirable Effects

Azithromycin is well tolerated with low incidence of side effects. In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain.

Adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency are listed below. The frequency grouping is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from available data).

OVERDOSE AND TREATMENT

Symptoms

Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhea.

Treatment

In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.

STORAGE CONDITION

In a dry place, below 30°C, protect from light.

SHELF-LIFE

36 months from the manufacturing date.