COMPOSITIONS :
Azithromycin Dihydrate Dry syrup 200 mg/5 ml, each 5 ml (a measurement spoonful) contains : Azithromycin dihydrate equivalent to Azithromycin 200 mg.
DESCRIPTIONS :
Azithromycin Dihydrate with Azithromycin dihydrate (equivalent with Azithromycin) as active ingredient is available in film coated caplet 500 mg, dry syrup 200 mg/5 ml and powder for infusion 0.5 g.
INDICATIONS :
Azithromycin Dihydrate Film coated caplet and dry syrup :
Azithromycin Dihydrate is indicated for the treatment of patients with mild to moderate infections (i.e., pneumonia) caused by susceptible strains of the designated microorganisms in the spesific conditions listed as follow :
Lower respiratory tract : Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.
Community-acquired pneumonia of mild severity due to Streptoccocus pneumoniae or Haemophilus influenzae in patients appropriate for outpatient oral therapy.
Upper respiratory tract : Streptococcal pharyngitis/tonsillitis : As an alternative to first-line therapy of acute pharyngitis/tonsillitis due to Streptoccocus pyogenes occuring in individuals who cannot use the 1st-line therapy.
Skin and skin structure : Uncomplicated skin and skin structure infections due to Staphylococus aureus, Streptococcus pyogenes or Streptococcus agalactiae. Abscesses usually required surgical drainage.
Sexually transmitted diseases : Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis.
Azithromycin, at the recommended dose, should not be relied upon to treat qonorrhea or syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating gonnorrhea or syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these disease should be initiated if infection is confirmed.
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to Azithromycin. Therapy with Azithromycin may be initiated before results of these tests are known; the results become available, antimicrobial therapy should be adjusted accordingly.
DOSAGE AND ADMINISTRATIONS :
Azithromycin Dihydrate Film coated caplet and dry syrup :
Azithromycin Dihydrate should be administered as a single daily dose. The period of dosing with regard to infection is given below.
Adults (including elderly) :
For the treatment of sexually transmitted diseases caused by Chlamydia trachomatis, Haemophilus ducreyi, or susceptible Neisseria gonorrhoeae the dose is 1000 mg as a single oral dose.
For all other indications in which the oral formulation is administered, the total dosage of 1500 mg should be given as 500 mg daily for 3 days.
Elderly patients may be more susceptible to development of torsades de pointes arrhythmia than younger patients (see WARNINGS AND PRECAUTIONS).
Children :
There is no information on children less than 6 months.
The total dose of 30 mg/kg should be given as a single daily dose of 10 mg/kg or as an alternative, given over 5 days with single daily dose of 10 mg/kg dose on day 1, then 5 mg/kg on days 2 – 5.
Azithromycin Dihydrate Dry syrup should be administered according to the guide provided below :
| Weight (kg) | 3-day regimen | 5-day regimen |
| 15 – 25 | 200 mg (5 ml) once daily on days 1 – 3 | 200 mg (5 ml) once a day on day 1, then 100 mg (2.5 ml) once daily on days 2 – 5 |
| 26 – 35 | 300 mg (7.5 ml) once daily on days 1 – 3 | 300 mg (7.5 ml) once a day on day 1, then 150 mg (3.75 ml) once daily on days 2 – 5 |
| 36 – 45 | 400 mg (10 ml) once daily on days 1 – 3 | 400 mg (10 ml) once a day on day 1, then 200 mg (5 ml) one daily on days 2 – 5 |
| > 45 | Dose as per adults | |
Azithromycin can be taken with or without food.
Patients with renal impairment :
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 – 80 ml/minute). Caution should be exercised when Azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/minute).
Patients with hepatic impairment :
The same dosage as in patients with normal hepatic function may be used in patients with mild to moderate hepatic impairment.
Preparation of Azithromycin Dihydrate Dry syrup :
Add 8 ml drinking water then shake till evenly suspended. Keep tightly closed. After mixing, store suspension below 30°C and use within 5 days.
Azithromycin Dihydrate Powder for Infusion :
Adults :
Treatment of CAP due to the indicated organisms :
Recommended dose : 500 mg IV as a single daily dose for at least 2 days. Intravenous therapy should be followed by oral Azithromycin at a single daily dose of 500 mg to complete a 7 to 10 days course of therapy. The timing of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response.
Treatment of PID due to the indicated organisms :
Recommended dose : 500 mg IV as a single dose for 1 or 2 days. Intravenous therapy should be followed by Azithromycin by the oral route at a single daily dose of 250 mg to complete a 7 days course of therapy. The time of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial anaerobic agent may be administered in combination with Azithromycin.
OVERDOSAGE :
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
CONTRAINDICATIONS :
Patients with hypersensitivity to Azithromycin, Erythromycin or any macrolide antibiotics.
WARNINGS AND PRECAUTIONS :
As with Erythromycin and other macrolides, rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal) and dermatologic reactions including Steven-Johnson Syndrome and toxic epidermal necrolysis (rarely fatal), have been reported. Some of these reactions with Azithromycin have resulted in recurrent symptom and required a longer period of observation and treatment.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physician should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
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.
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic nercrosis and hepatic failure have been reported, some of which have resulted in death. Discontinue Azithromycin immediately if signs and symptoms of hepatitis occur.
In patients with mild (Class A) to moderate (Class B) hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of Azithromycin compared to those with normal hepatic function. In these patients urinary recovery of Azithromycin appears to increase, perhaps to compensate for reduced hepatic clearance. Hence no dose adjustment is recommended for patients mild to moderate hepatic impairment.
In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotic. 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-administered.
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
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 Clostridium difficile.
Clostridium difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of Clostridium 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 Clostridium difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of Clostridium difficile and surgical evaluation should be instituted as clinically indicated.
Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes infections and the prophylaxis of rheumatic fever. Azithromycin is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to Azithromycin, susceptible test should be performed when patients are treated with Azithromycin. Data establishing efficacy of Azitromycin in subsequent prevention of rheumatic fever are not available. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physician should aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for outpatient oral therapy because of moderate to severe illness or risk factors such as any of the following :
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).
In patients with severe renal impairment (GFR < 10 ml/minute) a 33% increase in systemic exposure to Azithromycin was observed.
Due to the sucrose content, this medicinal product is not indicated for persons with fructose intolerance (hereditary fructose intolerance), glucose-galactose malabsorption or saccharase-isomaltase deficiency.
No dose adjustment is needed in patients with mild renal impairment (creatinine clearance > 40 mg/minute) but there are no data regarding Azithromycin usage in patients with more severe renal impairment.
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 (see ADVERSE REACTIONS), therefore caution is required when treating :
Patients with congenital or documented QT prolongation.
Patients currently receiving treatment with other active substance known to prolong QT interval such as antiarrhytmics of classes IA and III, antipsychotic agents, antidepressants and Fluoroquinolones.
Patients with electrolyte disturbance, particularly in cases of hypokalemia and hypomagnesemia.
Patients with clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency.
Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Pregnancy and lactation :
Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentration. In these studies, no evidence of harm to the fetus due to Azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant woman. Because animal reproduction studies are not always predictive of human response, Azithromycin should be used during pregnancy only if clearly needed.
Azithromycin has been reported to be excreted 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.
In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of Azithromycin. The relevance of this finding to human is unknown.
Effect 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.
DRUG 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 30%. In patients receiving both Azithromycin and Antacids, the drugs should not be taken simultaneously.
Cetirizine
In healthy volunteers, co-administration of a 5-day regimen of Azithromycin with Cetirizine 20 mg at a steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine (Dideoxyinosine)
Co-administration of 1200 mg/day Azithromycin with 400 mg/day Didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of Didanosine as compared with placebo.
Digoxin
Many patients have received co-administration of Azithromycin and cardiac glycosides and no interactions have been reported.
Concomitant administration of macrolide antibiotic including Azithromycin with P-glycoprotein substrate such as Digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if Azithromycin and P-gp substrates such as Digoxin are administered concomitantly the possibility of elevated serum Digoxin concentrations should be considered. Clinical monitoring and possibly serum Digoxin concentrations should be considered and after its discontinuation are necessary.
Zidovudine
Single 1000 mg doses and multiple 1200 mg or 600 mg doses of Azithromycin had little effect on the plasma pharmacokinetic or urinary excretion of Zidovudine or its glucuronide metabolite.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with Erythomycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with Azithromycin.
Ergot
Due to the theoretical possibility of ergotism, the concurrent use of Azithromycin with ergot derivatives is not recommended.
Atorvastatin
Co-administration of Atorvastatin (10 mg daily) and Azithromycin (500 mg daily) did not alter the plasma concentrations of Atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post marketing cases of rhabdomyolysis in patients receiving Azithromycin with Statins have been reported.
Carbamazepine
In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of Carbamazepine or its active metabolite in patients receiving concomitant Azithromycin. Cimetidine
In a pharmacokinetic study investigating the effects of a single dose of Cimetidine, given 2 hours before Azithromycin, on the pharmacokinetics of Azithromycin, no alternatif of Azithromycin pharmacokinetic was seen.
Coumarin-Type Oral Anticoagulants
In pharmacokinetic interaction study, Azithromycin did not alter the anticoagulant effect of a single 15-mg dose of Warfarin administered to healthy volunteers. There have been reports received in the postmarketing period of potentiated anticoagulation subsequent to co-administration of Azithromycin and Coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when Azithromycin is used in patients receiving Coumarin-type oral anticoagulants.
Cyclosporin
In a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of Azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of Cyclosporin, the resulting Cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before concurrent administration of these drugs. If co-administration is necessary, Cyclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz
Co-administration of a 600 mg single dose of Azithromycin and 400 mg Efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole
Co-administration of a single dose of 1200 mg Azithromycin did not alter the pharmacokinetics of a single dose of 800 mg Fluconazole. Total exposure and half-life of Azithromycin were unchanged by the coadministration of Fluconazole, however, a clinically insignificant decrease in Cmax (18%) of Azithromycin was observed.
Indinavir
Co-administration of a single dose of 1200 mg Azithromycin had no statistically significant effect on the pharmacokinetics of Indinavir administered as 800 mg three times daily for 5 days.
Methylprednisolone
In a pharmacokinetic interaction study in healthy volunteers, Azithromycin had no significant effect on die pharmacokinetic of Methylprednisolone.
Midazolam
In healthy volunteers, co-administration of Azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of Midazolam.
Nelfinavir
Co-administration of Azithromycin (1200 mg) and Nelfinavir at steady state (750 mg three times daily) resulted in increased Azithromycin concentration. No clinically significant adverse effects were observed and no dose adjustment is required.
Rifabutin
Co-administration of Azithromycin and Rifabutin did not affect the serum concentrations of either drug. Sildenafil
In normal healthy volunteers, there was no evidence of an effect of Azithromycin (500 mg daily for 3 days) on the AUC and Cmax of Sildenafil or its major circulating metabolite.
Terfenadine
Pharmacokinetic studies have reported no evidence of an interaction between Azithromycin and Terfenadine. There have been cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred. Theophylline
There is no evidence of a clinically significant pharmacokinetic interaction when Azithromycin and Theophylline are co-administered to healthy volunteers.
Triazolam
In 14 healthy volunteers, co-administration of Azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg Triazolam on day 2 had no significant effect on any of the pharmacokinetic variables for Triazolam compared to Triazolam and placebo.
Trimethoprim/Sulfamethoxazole
Co-administration of Trimethoprim/Sulfamethoxazole DS (160 mg/800 mg) for 7 days with Azithromycin 1200 mg on day 7 had no significant effect on peak concentration, total exposure or urinary excretion of either Trimethoprim or Sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.
ADVERSE REACTIONS :
Infections and infestations : Moniliasis and vaginitis.
Blood and lymphatic system disorders : Thrombocytopenia.
Immune system disorder : Anaphylaxis (rarely fatal).
Metabolism and nutrition disorder : Anorexia.
Psychiatric disorder : Aggressive reaction, nervousness, agitation and anxiety.
Nervous system disorder : Dizziness, convulsions (as seen with other macrolides), headache, hyperactivity, hypoesthesia, paresthesia somnolence and syncope.
Ear and labyrinth disorder : Deafness, tinnitus, hearing impaired, vertigo.
Cardiac disorder : Palpitations and arrhytmias including ventricular tachycardia.
Vascular disorder : Hypotension.
Gastrointestinal disorders : Vomiting/diarrhea (rarely resulting in dehydration), dyspepsia, constipation, pseudomembranous colitis, pancreatitis and rare reports of tongue discoloration.
Hepatobiliary disorder : Hepatitis and cholestatic jaundice have been reported, as well as rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death.
Skin and subcutaneous tissue disorders : Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria and angioedema. Rarely, serious skin reactions including erythema multiforme, Steven-Johnson syndrome and toxic epidermal necrolysis have been reported.
Musculoskeletal and connective tissue disorders : Arthralgia.
Renal and urinary disorders : Interstitial nephritis and acute renal failure.
General disorder and administration site conditions : Asthenia has been reported although a causal relationship has not been established; fatigue and malaise.
PRESENTATIONS :
Azithromycin Dihydrate Dry syrup 200 mg/5 ml Box, 1 bottle @ 15 ml
Reg. No. GKL1102344438A1
STORAGE :
Azithromycin Dihydrate Dry syrup :
STORE BELOW 25°C AND DRY PLACE
After mixing, store suspension below 30°C and use within 5 days.
Stable reconstitution solution within 24 hours when stored below 30°C. When reconstituted as directed, chemical and physical solubility stable for 24 hours under the temperature of 30°C or for 7 days if stored at refrigerator temperature (2 – 8)°C.
ON MEDICAL PRESCRIPTION ONLY
Manufactured by :
BERNOFARM
Sidoarjo – Indonesia
