Composition and excipients:

Each AZITHROMYCIN IBN HAYYAN F.C. Tablet contains:

active ingredients: Azithromycin 500 mg ( as dihydrate).

inactive ingredients:

* Core: Prosolv,  Sodium Starch Glycolate, Magnesium Stearate, Cross Carmellose Sodium, Talc, Colloidal anhydrous silica, Microcrystalline Cellulose.

*Film: Hypromellose, Talc, Polyethylene Glycol,  and Titanium dioxide.

Each Azithromycin IBN HAYYAN capsule contains:

active ingredients: Azithromycin 250 mg ( as dihydrate).

inactive ingredients: Lactose, corn starch, magnesium stearate, sodium lauryl sulfate.

Each 5ml of AZITHROMYCIN IBN HAYYAN oral suspension after  reconstitution contains:

active ingredients: Azithromycin 200 mg of ( as dihydrate ) .

inactive ingredients: Sugar, Xanthan Gum, Sodium benzoate, Sodium citrate, citric acid  and Orange flavor.

Pharmacological properties and mechanism of action:

Azithromycin is a macrolide antibiotic derived from erythromycin. It acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

– Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Microbiology:

Azithromycin  is effective against a wide variety of the following bacteria organisms :

– Aerobic Gram-Positive Microorganisms: such as  Staphylococcus aureus , Streptococcus agalactiae ,   Streptococcus pneumoniae , and Streptococcus pyogenes .

–  Aerobic Gram-Negative Microorganisms: such as  Haemophilus influenzae, Haemophilus ducreyi, Moraxella catarrhalis, and Neisseria gonorrhoeae.

–  Other microorgaisms: such as Chlamydia trachomatis , Chlamydia pneumoniae, and mycoplasma  pneumoniae.

Notes:  Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.

– Beta-lactamase production should have no effect on azithromycin activity.

Pharmacokinetics:

Absorption: The absolute bioavailability of azithromycin 250 mg capsules is 38%.

When a single 500 mg dose of azithromycin (two 250 mg capsules) is given with or without a high fat meal, food increases C_max by 23% but had no effect on AUC.

When azithromycin oral suspension  is  administered with food, the rate of absorption (C _max) is increased by 56 % and AUC is unchanged.

The AUC of azithromycin was unaffected by co-administration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the C_max was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

Distribution: The serum protein binding of azithromycin is variable, decreasing from 51% at 0.02 mg/ml to 7% at 2 mg/ml.

Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Greater azithromycin concentrations in tissues than in plasma or serum were observed. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of Azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity.

Azithromycin concentrates highly in the lungs and tonsils where its concentration in tonsils is more than 100-fold greater than in serum after two doses of 250 mg each, separated by 12 hours. Azithromycin also exists in the skin, cervix, sputum with a lower concentrations.

The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder).

– Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 mg/ml) in the presence of non-inflamed meninges.

– Metabolism & elimination: Azithromycin is eliminated by Biliary route, as unchanged drug. Over the course of a week, approximately 6% of the administered dose appears as unchanged in urine. In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. The terminal elimination half-life is about 68 hours.

Special Populations

Renal Insufficiency: Following the oral administration of a single 1,000 mg dose of azithromycin, mean C_max increased by 5.1% in subjects with mild to moderate renal impairment (GFR 10 to 80 ml/min). The mean C_max increased by 35%, in subjects with severe renal impairment (GFR <10 ml/min) compared to subjects with normal renal function (GFR >80 ml/min).

Hepatic Insufficiency: The pharmacokinetics of azithromycin 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 designated microorganisms in specific conditions. As recommended dosages, durations of therapy and applicable patient populations vary among these infections.

Adults:

– Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

– Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy.

– Pharyngitis/tonsillitis caused by streptococcus pyogenes ( as an alternative to pencillin which is the first line therapy) in individuals who cannot use pencillin.

Note: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection 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, susceptibility tests should be performed when patients are treated with Azithromycin. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.

-Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical

drainage.

-Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.

-Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). The efficacy of azithromycin in the treatment of chancroid in women has not been established.

– Azithromycin, at the recommended dose, should not be relied upon to treat 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 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 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; once the results become available, antimicrobial therapy should be adjusted accordingly.

Children:

– Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae

– Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy.

– Pharyngitis/tonsillitis caused by streptococcus pyogenes ( as an alternative to pencillin which is the first line therapy) in individuals who cannot use pencillin.

Note: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection 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, susceptibility tests should be performed when patients are treated with Azithromycin. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.

Contraindications:

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotic.

Warnings & Precautions:

– This drug should be used with caution in individuals with history of arrhythmias and  prolonged QT intervals.

– Pregnancy 🙁 category B) : There are no adequate studies of Azithromycin in pregnant women, so it should be used during pregnancy only if clearly needed.

– Breastfeeding: It is not known whether azithromycin is excreted in human milk, so caution should  be exercised when azithromycin is administered to a nursing woman.

– Pediatric use:

– Safety and effectiveness in the treatment of pediatric patients with acute otitis media under 6 months of age have not been established.

– Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established.

– Safety and effectiveness in the treatment of pediatric patients with community-acquired pneumonia under 6 months of age have not been established. Safety and effectiveness for pneumonia due to Chlamydia pneumoniae and Mycoplasma pneumoniae were documented in pediatric clinical trials. Safety and effectiveness for pneumonia due to Haemophilus influenzae and Streptococcus pneumoniae were not documented bacteriologically in the pediatric clinical trial due to difficulty in obtaining specimens. Use of azithromycin for these two microorganisms is supported, however, by evidence from adequate and well-controlled studies in adults.

Pharyngitis/Tonsillitis: Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under 2 years of age have not been established.

– Hepatic Impairment: Because Azithromycin is principally eliminated via the liver, caution should be exersiced when it is administrated to patients with impaired hepatic function

– 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).The mean Cmax  and AUC  increased 61% and 35%, respectively in subjects with severe renal impairment (GFR<10ml/min).

– Treatment with macrolides 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 pseudomembranous colitis.” Pseudomembranous colitis is associated by occurring diarrhea and it may range in severity from mild to life-threatening. mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone.

– Azithromycin should not be used in patients with pneumonia (adults or in pediatric patients) 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 (including immunodeficiency or functional asplenia).

– 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.

Adverse reactions:

– most of the side effects are mild to moderate in severity and are reversible upon discontinuation of the drug . Most of the side effects leading to discontinuation  are related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, loose stools, and abdominal pain. Rarely but potentially serious side effects are angioedema and cholestatic jaundice.

-Occurrence of  ventricular arrhythmias  has been reported with macrolide antibiotics, including ventricular tachycardia and torsade de points, in individuals with prolonged QT intervals.

Drug  interactions :

– when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised:

Antacids: Aluminum- and magnesium-containing antacids reduce the peak serum concentration of Azithromycin.

Cimitidine: it is advisable to take it two hours before taking Azithromycin.

Nelfinavir: when administered in conjunction with Azithromycin, close monitoring for side effects resulting , such as liver enzyme abnormalities and hearing impairment, is warranted.

Theophylline : concurrent use of Azithromycin and theophylline is associated with increased serum concentrations of theophylline.

Warfarin: Concurrent use of Azithromycin and warfarin is associated with increased anticoagulant effects. Therefore, careful monitoring of prothrombin time is important in all patients treated with azithromycin and warfarin concomitantly.

Digoxin—elevated serum digoxin levels.

Ergotamine or dihydroergotamine–acute ergot toxicity .

Triazolam--decrease the clearance of triazolam and thus may increase the pharmacologic effect of triazolam.

Drugs metabolized by the cytochrome P 450 system–elevations of serum carbamazepine, cyclosporine, hexobarbital, and phenytoin levels.

Dosage and Administration:

Adults:

Azithromycin ( tablets and capsules)  can be taken with or without food.

– Community-aquired pneumonia of mild severity, Pharyngitis/tonsillitis (as second-line therapy) and uncomplicated skin and skin structure infections is: 500 mg as a single dose on the first day followed by 250 mg once daily on Days 2 through 5.

– mild to moderate acute bacterial exacerbations of chronic obstructive pulmonary disease is either 500 mg per day for 3 days or 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5.

– Genital ulcer disease due to haemophilus ducreyi (chancroid) and non-gonococcal urethritis and cervicitis due to C. trachomatis : a single 1 g (1000 mg) dose of Azithromycin. This dose can be administered as four 250 mg capsules.

– urethritis and cervicitis due to neisseria gonorrhoeae: a single 2 gram (2000 mg) dose of Azithromycin.

Renal Insufficiency: No dosage adjustment is recommended for subjects with renal impairment (GFR < 80 ml/min). Caution should be exercised when azithromycin is administered to subjects with severe renal impairment.

Hepatic Insufficiency: No dose adjustment recommendations can be made in patients with impaired hepatic function.

– No dosage adjustment is recommended based on age or gender.

Children:

Azithromycin for oral suspension can be taken with or without food.

– Acute Otitis Media: The recommended dose of Azithromycin for oral suspension 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.

– Community-Acquired Pneumonia: The recommended dose of Azithromycin for oral  suspension is 10mg/kg as a single dose on the first day followed by 5 mg/kg on Days 2 through 5.

– Pharyngitis/Tonsillitis: The recommended dose is 12 mg/kg once daily for 5 days.

– Based on pediatric pharmacokinetic data, a dose of 20 mg/kg would be similar to the adult dose of 1200 mg but with a higher C_max.

– For children weighing less than 15 kg, azithromycin suspension should be measured as closely as possible. For children weighing 15 kg or more, azithromycin suspension should be administered according to the guide provided below:

 

AZITHROMYCIN SUSPENSION 30 mg/kg Total Treatment Dose
Weight (kg)	3-Day Regimen	5-Day Regimen
<15	10 mg/kg once daily on days 1-3	10 mg/kg on day 1, then 5 mg/kg once daily on days 2-5
15-25	200 mg (5 ml) once daily on days 1-3	200 mg (5 ml) 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) 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) on day 1, then 200 mg (5 ml) once daily on days 2-5
>45	Dose as per adults	Dose as per adults

The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as asingle dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, eight patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.

Storage:

– Store capsules at a temperature below  30 C°.

– Store tablets at a temperature between 15-30 Cْ.

– store dry powder of oral suspension below 30°C , away from moisture .

– After constituation store suspension at temperature below 30° C. use it within 10 days. Discard after full dosing is completed.

– shake the bottle well before each use .

– Keep this medicine out of the reach of children

Packing:

Azithromycin – Ibn – Hayyan 200 mg / 5 ml : a bottle contains dry powder  for oral suspension of 15 , 30 ml after

reconstitution.

Azithromycin – Ibn – Hayyan 250 mg: a box contains 6 capsules.

Azithromycin – Ibn – Hayyan 500 mg: a box contains 3 f.c. tablets.