Ava-Azithromycin Product Monograph

ACTION AND CLINICAL PHARMACOLOGY

Azithromycin, a macrolide antibiotic of the azalide subclass, exerts its antibacterial action by binding to the 50s ribosomal subunits of susceptible bacteria and suppressing protein synthesis.

Following oral administration, azithromycin is rapidly absorbed (T_max = 2-3 hours) and distributed widely throughout the body. Rapid movement of azithromycin from blood into tissue results in significantly higher azithromycin concentrations in tissue than in plasma (up to 50 times the maximum observed concentration in plasma). The absolute bioavailability is approximately 37%. When azithromycin suspension was administered with food to 28 adult healthy male subjects, the rate of absorption (C_max) was increased by 56% while the extent of absorption (AUC) was unchanged.

Food does not affect the absorption of azithromycin in the tablet dosage form. Azithromycin tablets and powder for oral suspension can be taken with or without food.

ADULT PHARMACOKINETICS

Plasma concentrations of azithromycin decline in a polyphasic pattern, resulting in an average terminal half-life of 68 hours. The prolonged half-life is likely due to extensive uptake and subsequent release of drug from tissues. Over the dose range of 250 to 1000 mg orally, the serum concentrations are related to dose. The long tissue half-life and large volume of distribution result from intracytoplasmic uptake and storage in lysosomal phospholipid complexes.

In adults, the following pharmacokinetic data have been reported:

^a0-48 hr, ^b 0-last

Biliary excretion of azithromycin, predominantly as unchanged drug, is a main route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in the urine.

Intravenous Administration

In patients hospitalized with community-acquired pneumonia (CAP) receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the median maximum concentration (C_max) achieved was 3.00 mcg/mL (range: 1.70-6.00 mcg/mL) while the 24-hour trough level was 0.18 mcg/mL (range: 0.07-0.60 mcg/mL) and the AUC₂₄ was 8.50 mcg·h/mL (range: 5.10-19.60 mcg·h/mL).

The median C_max, 24-hour trough and AUC₂₄ values were 1.20 mcg/mL (range: 0.89-1.36 mcg/mL), 0.18 mcg/mL (range:0.15-0.21 mcg/mL) and 7.98 mcg/mL (range:6.45-9.80 mcg·h/mL), respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with CAP that received the same 3-hour dosage regimen for 2-5 days.

^a 500 mg (2 mg/mL) for 2-5 days in CAP patients

^b 500 mg (1 mg/mL) for 5 days in healthy subjects

The average Cl_t and Vd values were 10.18 mL/min/kg and 33.3 L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000 mg doses given as 1 mg/mL over 2 hours.

Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin shows only an 8% increase in C_max but a 61% increase in AUC₂₄ reflecting the three-fold rise in C₂₄ trough levels.

In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenous dosage regimen for 5 days, the amount of administered azithromycin dose excreted in the urine in 24 hours was about 11% after the first dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral azithromycin administration.

SPECIAL POPULATIONS

Pediatric Pharmacokinetics:

Pharmacokinetics in children receiving a total dose of 30 mg/kg:

The table below shows mean pharmacokinetic parameters on day 5 in children 1 to 5 years and 5 to 15 years of age when azithromycin oral suspension was dosed in the absence of food at a total dose of 30 mg/kg delivered as 10 mg/kg on day 1 and 5 mg/kg on days 2-5.

Pharmacokinetics in children given a total dose of 30 mg/kg delivered as a single dose have not been studied.

Pharmacokinetics in children receiving a 60 mg/kg total dose:

Two clinical studies enrolled 35 and 33 children respectively aged 3-16 years with pharyngitis/tonsillitis to determine the pharmacokinetics and safety of azithromycin for oral suspension in children when given 60 mg/kg in divided doses delivered as 20 mg/kg/day over 3 days or 12 mg/kg/day over 5 days with a maximum daily dose of 500 mg.

The following table shows pharmacokinetic data in the subset of children who received a total dose of 60 mg/kg. In both studies azithromycin concentrations were determined over a 24 hour period following the last daily dose.

^a Arithmetic means

^b Maximum weight for 3 day regimen was ≤ 25 kg and for 5 day regimen was ≤ 41.7 kg

Similarity of overall exposure (AUC _0-∞) between the 3 and the 5 day regimen is unknown.

Geriatrics

When studied in healthy elderly subjects from age 65 to 85 years, 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.

Renal Insufficiency

Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean C_max and AUC_0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean C_max and AUC_0-120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min) (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of oral azithromycin compared to those with normal hepatic function. In these patients urinary recovery of azithromycin appears to increase. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Nonetheless, since the liver is the principal route of elimination for azithromycin, the use of oral azithromycin preparations should be undertaken with caution in patients with impaired hepatic function.

INDICATIONS AND CLINICAL USE

AVA-AZITHROMYCIN FOR ORAL ADMINISTRATION

Ava-Azithromycin (azithromycin monohydrate) is indicated for treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the following diseases and specific conditions. As recommended dosages, durations of therapy, and applicable patient populations vary among these infections, see DOSAGE AND ADMINISTRATION for specific dosing recommendations.

Because some strains are resistant to azithromycin, when applicable, appropriate culture and susceptibility tests should be initiated before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with Ava-Azithromycin may be initiated before results of these tests are known; once the results become available, antibiotic treatment should be adjusted accordingly.

ADULTS

Pharyngitis and Tonsillitis

Pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) occurring in individuals who cannot use first line therapy.

Note: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin is often effective in the eradication of susceptible strains of streptococci from the oropharynx. However, data establishing the efficacy of azithromycin in the subsequent prevention of rheumatic fever are not available at present.

Acute Bacterial Exacerbations of Chronic Obstructive Pulmonary Disease Acute bacterial exacerbations of chronic obstructive pulmonary diseases caused by Hæmophilus influenzæ, Moraxella catarrhalis, or Streptococcus pneumoniæ.

Community-Acquired Pneumonia

Community-acquired pneumonia caused by Streptococcus pneumoniæ, Hæmophilus influenzæ, Mycoplasma pneumoniæ or Chlamydia pneumoniæ in patients for whom oral therapy is appropriate.

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).

Uncomplicated Skin and Skin Structure Infections

Uncomplicated skin and skin structure infections caused by Staphylococcus aureus, Streptococcus pyogenes or Streptococcus agalactiæ.

Genitourinary Tract Infections

Urethritis and cervicitis due to Neisseria gonorrhoeæ or Chlamydia trachomatis. Genital ulcer disease in men due to Hæmophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.

Patients 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 diseases should be initiated if infection is confirmed.

CHILDREN

(see DOSAGE AND ADMINISTRATION; PRECAUTIONS, Use in Children; PHARMACOLOGY, Clinical Trials in Pediatric Patients.)

Treatment

Acute otitis media:

Acute otitis media caused by Haemophilus influenzae (β-lactamase positive and negative strains), Moraxella catarrhalis or Streptococcus pneumoniae. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION.)

Pharyngitis and tonsillitis:

Pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) occurring in individuals who cannot use first line therapy. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION.)

NOTE: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes pharyngitis, including the prophylaxis of rheumatic fever. Azithromycin is often effective in the eradication of susceptible strains of streptococci from the oropharynx. However, data establishing the efficacy of azithromycin in the subsequent prevention of rheumatic fever are not available at present.

Community-acquired pneumonia:

Community-acquired pneumonia caused by Haemophilus influenzae, Streptococcus pneumoniae, Mycoplasma pneumoniae or Chlamydia pneumoniae in patients for whom oral

therapy is appropriate. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION.)

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 cystic fibrosis, patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).

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.

CONTRAINDICATIONS

Ava-Azithromycin (azithromycin monohydrate) is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibacterial agent, or to any excipient listed in PHARMACEUTICAL INFORMATION.

WARNINGS

Serious allergic reactions, including angioedema, anaphylaxis and dermatological reactions including Steven’s Johnson syndrome and toxic epidermolysis have been reported rarely (with rare reports of fatalities), in patients on azithromycin monohydrate therapy (see CONTRAINDICATIONS). Allergic reactions may occur during and soon after treatment with azithromycin. 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. 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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents including azithromycin and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents 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 colitis". After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and

electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.

In the absence of data on the metabolism and pharmacokinetics in patients with lysosomal lipid storage diseases (e.g., Tay-Sachs disease, Niemann-Pick disease) the use of azithromycin in these patients is not recommended.

Rare cases of acute hepatic necrosis requiring liver transplant or causing death have been reported in patients following treatment with oral azithromycin.

Intramuscular use of azithromycin is not recommended; extravasation of drug into the tissues may cause tissue injury.

PRECAUTIONS

GENERAL

Since liver is the major route of elimination for azithromycin, the use of oral azithromycin preparations should be undertaken with caution in patients with impaired hepatic function.

Due to limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing oral azithromycin in these patients (see ACTIONS AND CLINICAL PHARMACOLOGY, SPECIAL POPULATIONS, Renal Insufficiency).

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect has been reported with azithromycin and can not be completely ruled out. There is information that ‘QT Related Adverse Events’ may occur in some patients receiving azithromycin, although these adverse events have not been reported in clinical trials with azithromycin. There have been spontaneous reports from post-marketing experience of prolonged QT interval and torsades de pointes (see ADVERSE REACTIONS – POSTMARKETING EXPERIENCE). These include but are not limited to: one AIDS patient dosed at 750 mg to 1 g daily experienced prolonged QT interval and torsades de pointes; a patient with previous history of arrythmias who experienced torsades de pointes and subsequent myocardial infarction following a course of azithromycin therapy; and a pediatric case report of prolonged QT interval experienced at a therapeutic dose of azithromycin which reversed to normal upon discontinuation.

SPECIAL POPULATIONS

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. In animal studies at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day), no evidence of harm to the fetus due to azithromycin was found (see: TOXICOLOGY, Reproductive Studies and Fetotoxicity Teratology). Ava-Azithromycin should not be used during pregnancy unless the expected benefit to the mother outweighs any potential risk to the fetus.

Nursing Women:

There are no data on secretion in breast milk. Azithromycin should not be used in the treatment of lactating women unless the expected benefit to the mother outweighs any potential risk to the infant. Because azithromycin may accumulate in breast milk over time with continued Ava-Azithromycin therapy, if the lactating mother is treated with Ava-Azithromycin, the breast milk should be expressed and discarded during treatment.

Pediatrics:

(see ACTIONS AND CLINICAL PHARMACOLOGY; INDICATIONS AND CLINICAL USE; DOSAGE AND ADMINISTRATION)

Acute Otitis Media: Safety and efficacy in the treatment of children with otitis media under 6 months of age have not been established (see DOSAGE AND ADMINISTRATION).

Community-acquired pneumonia: Safety and efficacy in the treatment of children with community-acquired pneumonia under 6 months of age have not been established (see DOSAGE AND ADMINISTRATION).

Pharyngitis and tonsillitis: Safety and efficacy in the treatment of children with pharyngitis and tonsillitis under 2 years of age have not bee established (see DOSAGE AND ADMINISTRATION).

Studies evaluating the use of repeated courses of therapy have not been conducted. Safety data with the use of azithromycin dihydrate at doses higher than proposed and for durations longer than recommended are limited to a small number of immunocompromised children who underwent chronic treatment.

In animal studies, treatment with azithromycin is associated with accumulation in various tissues, including the extra-cranial neural ganglia (i.e., retina and sympathetic nervous system). Tissue accumulation is both dose and time dependent, and is associated microscopically with the development of phospholipidosis (intra-lysosomal drug phospholipid complexes). The only evidence in animals that azithromycin is associated with alterations of intracellular phospholipid metabolism has been the documentation of small increases in phospholipid content after prolonged treatment (6 months) or exaggerated doses. Phospholipidosis has been observed at total cumulative doses only 2 multiples of the clinical dose. One month after withdrawal of treatment the concentration of azithromycin and the presence of phospholipidosis in tissue, including the retina, is at or near predose levels.

No data exist in humans in regard to the extent of accumulation, duration of exposure, metabolism or excretory mechanisms of azithromycin in neural tissue such as the retina and the cochlea. Rare cases of hearing loss have been reported (see ADVERSE REACTIONS).

No data are available on the metabolism and pharmacokinetics of azithromycin in children with lysosomal lipid storage diseases (see WARNINGS).

Prevention of Disseminated Mycobacterium Avium Complex (MAC) Disease

Safety and efficacy of Ava-Azithromycin for the prevention of MAC in children have not been established.

Limited safety data are available for 24 children 5 months to 14 years of age (mean 4.6 years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 186.7 days (range 13-710 days) at doses of <5 to 20 mg/kg/day. Adverse events were similar to those observed in the adult population, most of which involved the gastrointestinal tract. While none of these children prematurely discontinued treatment due to a side effect, one child discontinued due to a laboratory abnormality (eosinophilia). Based on available pediatric pharmacokinetic data, a dose of 20 mg/kg in children would provide drug exposure similar to the 1200 mg adult dose but with a higher C_max.

Use in Elderly:

The pharmacokinetics in elderly volunteers (age 65 to 85) were similar to those in younger volunteers (age 18 to 40) for the 5-day oral therapeutic regimen. Dosage adjustment does not appear to be necessary for elderly patients with normal renal and hepatic function receiving treatment with this dosage regimen. Pharmacokinetic studies with intravenous azithromycin have not been performed in the elderly. Based on clinical trials, there appear to be no significant differences in safety or tolerance of intravenous azithromycin between elderly (age ≥65) and younger subjects (ages 16 to ≤64).

DRUG INTERACTIONS

Antacids

Aluminum and magnesium containing antacids (Maalox^®) reduce the peak serum levels but not the extent of azithromycin absorption. Ava-Azithromycin and these drugs should not be taken simultaneously.

Atorvastatin

In healthy volunteers, co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG CoA-reductase inhibition assay).

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.

Cetirizine

In healthy male volunteers, co-administration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Cimetidine

Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.

Coumarin-Type Oral Anticoagulants

In clinical trials, azithromycin did not affect the prothrombin time response to a single dose of warfarin.

During the post-marketing period, there have been reports of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants.

Although a causal relationship has not been established, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.

Cyclosporine

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 cyclosporine, the resulting cyclosporine C_max and AUC_0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Didanosine

Daily doses of 1200 mg azithromycin had no effect on the pharmacokinetics of didanosine.

Efavirenz

Efavirenz, when administered at a dose of 400 mg for seven days produced a 22% increase in the C_max of azithromycin administered as a 600 mg single dose. AUC was not affected.

Administration of a single 600 mg dose of azithromycin had no effect on the pharmacokinetics of efavirenz given at 400 mg doses for seven days.

Fluconazole

A single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single 800 mg oral dose of fluconazole.

Total exposure and half-life of 1200 mg azithromycin were unchanged and C_max had a clinically insignificant decrease (18%) by coadministration with 800 mg fluconazole.

Indinavir

A single dose of 1200 mg azithromycin had no significant effect on the pharmacokinetics of indinavir (800 mg indinavir t.i.d. for 5 days).

Midazolam

In healthy volunteers (n=12), 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

Coadministration of a single dose of 1200 mg azithromycin with steady-state nelfinavir (750 mg t.i.d.) produced an approximately 16% decrease in mean AUC_0-8 of nelfinavir and its M8 metabolite. C_max was not affected.

Coadministration of nelfinavir (750 mg t.i.d.) at steady-state with a single dose of 1200 mg azithromycin increased the mean AUC_0-∞ of azithromycin by 113% and mean C_max by 136%.

Dose adjustment of azithromycin is not recommended. However, close monitoring for known side effects of azithromycin, when administered in conjunction with nelfinavir, is warranted. Rifabutin

Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either drug.

Sildenafil

In normal healthy male volunteers, there was no evidence of a statistically significant effect of azithromycin (500 mg daily for 3 days) on the AUC, C_max, T_max, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite.

Theophylline

Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Azithromycin did not affect the pharmacokinetics of theophylline administered either as a single intravenous infusion or multiple oral doses at a recommended dose of 300 mg every 12 hours. There is one post-marketing report of supraventricular tachycardia associated with an elevated theophylline serum level that developed soon after initiation of treatment with Azithromycin. Until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving azithromycin and theophylline concomitantly.

Trimethoprim / Sulfamethoxazole

Following administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days to healthy subjects, coadministration of 1200 mg azithromycin on Day 7 had no significant effects on peak concentrations or total exposure or urinary excretion of either trimethoprim or sulfamethoxazole.

Serum concentrations of azithromycin following administration of a single 1200 mg dose after administration of trimethoprim/sulfamethoxazole DS for 7 days were similar to those produced following a 1200 mg dose of azithromycin in other studies.

Zidovudine

Single 1 g doses and multiple 1200 mg or 600 mg doses of azithromycin did not affect on the

plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine in peripheral blood mononuclear cells.

Concomitant Therapy

The following drug interactions have not been reported in clinical trials with azithromycin and no specific drug interaction studies have been performed to evaluate potential drug-drug interactions. Nonetheless, they have been observed with macrolide products, and there have been rare spontaneously reported cases with azithromycin and some of these drugs, in postmarketing experience. Until further data are developed regarding drug interactions, when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised both during and for a short period following therapy:

Digoxin: Elevation of digoxin levels.

Disopyramide: Increase in pharmacological effects.

Ergotamine or dihydroergotamine: Acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

Triazolam: Decreases in the clearance of triazolam and increases in the pharmacologic effect of triazolam.

Drugs metabolized by the cytochrome P450 system: Elevations of serum hexobarbital, cisapride, and phenytoin levels.

Antihistamines: Prolongation of QT intervals, palpitations or cardiac arrhythmias with concomitant administration of astemizole or terfenadine.

No data are available on the concomitant clinical use of azithromycin and gentamicin or other amphiphilic drugs which have been reported to alter intracellular lipid metabolism.

ADVERSE REACTIONS

GENERAL

The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with oral azithromycin dihydrate were of a mild and transient nature. Approximately 0.7% of both adult patients (n=3812) and children (n=2878) from the 5-day multiple dose clinical trials discontinued azithromycin dihydrate therapy because of drug related side effects. Among adults receiving azithromycin intravenously, 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%).

In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was 0.4%. In clinical trials in children given 30 mg/kg, orally either as a single dose (n= 487) or over 3 days, (n=1729) discontinuation from therapy due to treatment-related side effects

was approximately 1%.

Most of the side effects leading to discontinuation in patients on oral or intravenous therapy were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, along with abdominal pain, rashes and increases in aminotransferases and/or alkaline phosphatase levels in adult patients receiving intravenous azithromycin. Potentially serious treatment-related side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.

ORAL REGIMEN : ADULTS

Multiple-dose Regimens:

In adult patients, the most common treatment-related side effects in patients receiving the 3 or 5 day oral multiple-dose regimens of azithromycin dihydrate were related to the gastrointestinal system with diarrhea/loose stools (4-5%), abdominal pain (2-3%), vomiting (1%) and nausea (3-4%).

Treatment-related side effects that occurred with a frequency of 1% or less include:

Cardiovascular: hypertension

Gastrointestinal: dry mouth, esophagitis, gastroenteritis, rectal hemorrhage, cholestatic jaundice Genitourinary: mennorhagia, urinary frequency, vaginitis

Special senses: conjunctivitis

Nervous system: dizziness

Allergic: pruritus

Single 1-gram Dose Regimen:

In adult patients (n=904), side effects that occurred on the single one-gram dosing regimen of azithromycin dihydrate with a frequency greater than 1% included diarrhea (6.1%), nausea (4.9%), abdominal pain (4.9%), vomiting (1.7%), vaginitis (1.3%), loose stools (1.2%), and dyspepsia (1.1%).

Single 2-gram Dose Regimen:

Overall, the most common side effects in patients receiving a single 2-gram dose of azithromycin dihydrate were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of a 1% or greater included nausea (18.2%), diarrhea/loose stools (13.8%), vomiting (6.7%), abdominal pain (6.7%), vaginitis (2.2%), dyspepsia (1.1%), and dizziness (1.3%). The majority of these complaints were mild in nature.

INTRAVENOUS/ORAL REGIMEN : ADULTS

The most common side effects (greater than 1%) in adult patients who received sequential I.V./oral azithromycin in studies of community-acquired pneumonia were related to the gastrointestinal system: diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%). Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the site and/or during the infusion (6.5%) and local inflammation (3.1%).

In adult women who received sequential I.V./oral azithromycin in studies of pelvic inflammatory disease, the most common side effects (greater than 1%) were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most frequently reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was co-administered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%) and application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%).

Side effects that occurred with a frequency of 1% or less included:

Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis Nervous System: headache, somnolence

Allergic: bronchospasm

Special Senses: taste perversion

ORAL REGIMEN : CHILDREN

Single and Multiple-dose regimens:

In children enrolled in controlled clinical trials in acute otitis media and S. pyogenes pharyngitis, the type of side effects were comparable to those seen in adults (see below). Different side effect incidence rates for the dosage regimens recommended in children were observed:

Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. The incidence, based on dosing regimen, is described in the table below:

Community-Acquired Pneumonia: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting/nausea and rash. The incidence is described in the table below:

Pharyngitis/tonsillitis: For the recommended total dosage regimen of 60 mg/kg, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below:

Side effects that occurred with a frequency of 1% or less in patients included the following:

Cardiovascular: Palpitations, chest pains;

Gastrointestinal: Dyspepsia, flatulence, melena, constipation, anorexia, enteritis, loose stools, oral moniliasis and gastritis;

Genitourinary: Monilia, vaginitis and nephritis;

Hematologic and Anemia, leukopenia;

Lymphatic:

Nervous System: Dizziness, vertigo, somnolence, agitation, nervousness, insomnia and hyperkinesia;

General: Fatigue, face edema, fever, fungal infection, pain and malaise;

Respiratory: Cough increased, pharyngitis, pleural effusion and rhinitis;

Skin and Appendages: Eczema, fungal dermatitis, sweating and vesiculobullous rash;

Allergic: Allergic reaction, photosensitivity, angioedema, erythema multiforme, pruritus and urticaria;

Liver/Biliary: Liver function test abnormal, jaundice and cholestatic jaundice.

POSTMARKETING EXPERIENCE

The following adverse experience have been reported in patients under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain or in patients treated with significantly higher than the recommended doses for prolonged periods:

Allergic: Arthralgia, edema, anaphylaxis (with rare reports of fatalities), serum sickness, urticaria, vasculitis, angioedema, pruritus;

Cardiovascular: Cardiac arrhythmias (including ventricular tachycardia), palpitations, hypotension. There have been rare reports of QT prolongation and torsades de pointes in patients receiving therapeutic doses of azithromycin, including a pediatric case report of QT interval prolongation which reversed to normal upon discontinuation (see PRECAUTIONS).

Gastrointestinal: Anorexia, constipation, dehydration, vomiting/diarrhea rarely resulting in dehydration, pancreatitis, pseudomembranous colitis, rare reports of tongue discoloration;

General: Asthenia, paresthesia, fatigue, muscle pain;

Genitourinary: Interstitial nephritis, acute renal failure, nephrotic syndrome, vaginitis;

Hematopoietic: Thrombocytopenia

Liver/Biliary: Abnormal liver function including drug-induced hepatitis and cholestatic jaundice have been reported. There have also been rare cases of hepatic necrosis and hepatic failure, which have rarely resulted in death;

Nervous System: Aggressive reaction, anxiety, dizziness, hyperactivity, seizure, convulsions, nervousness, agitation and syncope

Skin/Appendages: Serious skin reactions including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis;

Special Senses: Hearing disturbances including hearing loss, deafness and / or tinnitus, vertigo, taste/smell perversion and/or loss, abnormal vision.

LABORATORY ABNORMALITIES

Oral therapy:

Adults:

Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials in patients were reported as follows:

With an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, monocytes, albumin and blood glucose, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT and AST (SGOT), BUN, creatinine, blood glucose, platelet count, eosinophils and monocytes.

With an incidence of less than 1%: leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, LDH and phosphate.

The majority of subjects with elevated serum creatine also had abnormal values at baseline.

When follow-up was provided, changes in laboratory tests appeared to be reversible.

In multiple-dose clinical trials involving more than 4500 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities, one for treatment-related elevated transaminases and triglycerides and one because of a renal function abnormality.

Children:

One-, Three- and Five-Day Regimens

Laboratory data collected from 64 subjects receiving azithromycin in comparative clinical trials employing the 1-day regimen (30 mg/kg as a single dose), 1198 and 169 subjects receiving azithromycin respectively employing the two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%. Similar results were obtained in subjects receiving the two 5-day regimens. Overall, 1948 and 421 patients were exposed to 30 mg/kg or 60 mg/kg, respectively in divided doses over 5 days. The data collected in the subset of azithromycin patients assessed for laboratory abnormalities were similar to those in all comparators combined with most clinically significant laboratory abnormalities occurring at incidences of 1-5%. In a single center clinical trial, a decrease in absolute neutrophils was observed in the range of 21-29% for azithromycin regimens of 30 mg/kg given either as a single dose or over 3 days, as well as the comparator. No patients had significant neutropenia defined as an absolute neutrophil count <500 cells/mm³ (see PHARMACOLOGY, Clinical Trials).

In clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

Intravenous Therapy:

With an incidence of 4-6%, elevated ALT, AST, and creatinine.

With an incidence of 1-3%, elevated LDH and bilirubin.

With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase.

In multiple dose clinical trials involving more than 750 patients treated with sequential I.V./oral azithromycin less than 2% of patients discontinued therapy because of treatment-related liver enzyme abnormalities.

When follow-up was provided, changes in laboratory tests appeared to be reversible for both oral and I.V. dosing.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Up to 15 grams cumulative dose of azithromycin dihydrate over 10 days has been administered in clinical trials without apparent adverse effect.

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.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

DOSAGE AND ADMINISTRATION

GENERAL

Hepatic Impairment:

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of oral azithromycin dihydrate compared to those with normal hepatic function. In these patients urinary recovery of azithromycin appears to increase. Hence no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Nonetheless, since the liver is the principal route of elimination for azithromycin, the use of oral azithromycin preparations should be undertaken with caution in patients with impaired hepatic function.

Renal Impairment:

No dosage adjustment of oral azithromycin preparations is recommended for subjects with mild to moderate (GFR 10-80 mL/min) renal impairment. The mean AUC0-120 was similar in subjects with GFR 10- 80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment. (see ACTIONS AND CLINICAL PHARMACOLOGY, SPECIAL Populations, Renal Insufficiency and PRECAUTIONS).

AVA-AZITHROMYCIN FOR ORAL THERAPY

ADULTS

Dosing in Relation to Food

Tablets: Ava-Azithromycin tablets can be taken with or without food.

Upper and Lower Respiratory Infections/Skin and Skin Structure Infections The recommended dose of Ava-Azithromycin for individuals 16 years of age or older in the treatment of mild to moderate acute bacterial exacerbations of chronic obstructive pulmonary disease due to the indicated organisms is either 500 mg per day for 3 days or 500 mg as a single dose on the first day followed by 250 mg once daily on days 2 through 5 for a total dose of 1.5 grams. The recommended dose of Ava-Azithromycin for the treatment of community-acquired pneumonia of mild severity, uncomplicated skin and skin structure infections, and for pharyngitis/tonsillitis (as second-line therapy) due to the indicated organisms is 500 mg as a single dose on the first day followed by 250 mg once daily on days 2 though 5 for a total dose of 1.5 grams.

Genitourinary Infections

The recommended dose of Ava-Azithromycin for the treatment of genital ulcer disease due to Hæmophilus ducreyi (chancroid) and nongonococcal urethritis and cervicitis due to C. trachomatis is a single 1 gram (1 000 mg) oral dose of Ava-Azithromycin. This dose can be administered as four 250 mg tablets.

The recommended dose of Ava-Azithromycin for the treatment of urethritis and cervicitis due to Neisseria gonorrhoeæ is a single 2 gram (2 000 mg) dose of Ava-Azithromycin. This dose can be administered as eight 250 mg tablets.

CHILDREN

Dosing in relation to FOOD:

Powder for Oral Suspension: Ava-Azithromycin (azithromycin monohydrate) Powder for Oral Suspension can be taken with or without food (see ACTION AND CINICAL PHARMACOLOGY).

Pediatric Dosing Guidelines:

The recommended total dose for children is 30 mg/kg for otitis media and community acquired pneumonia. For pharyngitis/tonsillitis, the recommended total dose is 60 mg/kg.

ACUTE OTITIS MEDIA:

The recommended dose of Ava-Azithromycin (azithromycin monohydrate) oral suspension for the treatment of children with acute otitis media is 30 mg/kg given as a single dose (not to exceed 1500 mg) or 10 mg/kg once daily for 3 days (not to exceed 500 mg/day) or 10 mg/kg as a single dose on the first day (not to exceed 500 mg/day) followed by 5 mg/kg/day on days 2 through 5 (not to exceed 250 mg/day). (See chart #1, 2 and 3 respectively below).

The safety of re-dosing azithromycin in children who vomit after receiving 30 mg/kg as a single 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.

COMMUNITY-ACQUIRED PNEUMONIA:

The recommended dose of Ava-Azithromycin (azithromycin monohydrate) for oral suspension for the treatment of children with community-acquired pneumonia is 10 mg/kg as a single dose on

the first day (not to exceed 500 mg/day) followed by 5 mg/kg on days 2 though 5 (not to exceed 250 mg/day). (See chart #3 below)

Effectiveness of the 3-day or 1-day regimen in children with community-acquired pneumonia has not been established.

PHARYNGITIS AND TONSILLITIS:

The recommended dose for children with pharyngitis and tonsillitis is 12 mg/kg once daily for 5 days (not to exceed 500 mg/day) (See chart #4 below).

PEDIATRIC DOSAGE GUIDELINES

BASED on BODY Weight

CHART #1

* Effectiveness of the 1-day regimen in children with community-acquired pneumonia has not been established.

CHART #2

*Effectiveness of the 3-day regimen in children with community-acquired pneumonia has not been established.

CHART #3

CHART # 4

RECONSTITUTION DIRECTIONS

Ava-Azithromycin, Powder for Oral Suspension:

Tap bottle to loosen powder. Add the directed volume of water. Shake well before each use. Oversized bottle provides shake space. Keep tightly closed. The table below indicates the volume of water to be used for reconstitution:

Use only the dosing device provided to measure the correct amount of suspension (see AVAILABILITY OF DOSAGE FORMS). The dosing device may need to be filled multiple times to provide the complete dose prescribed. Rinse the device with water after the complete daily dose has been administered.

Following constitution, and for use with the oral syringe, the supplied plastic stopper should be inserted into the neck of the bottle then sealed with the original closure.

PHARMACEUTICAL INFORMATION - TABLETS

DRUG SUBSTANCE

Common Name: Azithromycin Monohydrate Hemiethanolate

Chemical Name: 9-deoxo-9α-aza-9α-methyl-9α-homoerythromycin A monohydrate hemiethanolate

Structural Formula:

Molecular Formula: C₃₈ H₇₂ N₂ O₁₂ . H₂O. ¹/₂ CH₃CH₂OH

Molecular Weight: 790 (Hydrate solvate), 749 (Anhydrate)

Description: Azithromycin is a white to off-white crystalline powder. The solubility of azithromycin ethanolate hydrate in unbuffered water is <0.12 mg/mL. The powder is moderately hygroscopic.

pK_a: 8.48

Melting Point: 125°C

N

O

O

CH₃

OCH₃

H₃C

O

H₃C

H₃C

CH₃

CH₃

OH

O CH₃

HO N(CH₃)₂ . 2H₂O HO

H₃C

H₃C

HO

H₃C

CH₃

O

O

OH

H₂O x ¹/₂ CH₃CH₂OH

PHARMACEUTICAL INFORMATION – POWDER FOR ORAL SUSPENSION

DRUG SUBSTANCE

Proper name: Azithromycin Monohydrate

Chemical name: 9-deoxo-9α-aza-9α-methyl-9α-homoerythromycin A monohydrate.

Molecular formula: C₃₈H₇₂N₂O₁₂ ·H₂0

Molecular mass: 767.02

Structural formula:

Physicochemical properties:

Description: Azithromycin monohydrate is a white or slightly yellowish crystalline powder.

pKa: 9.0 to 11.0

COMPOSITION

TABLETS:

Ava-A

POWDER FOR ORAL SUSPENSION:

Ava-Azithromycin Powder for Oral Suspension contains azithromycin monohydrate equivalent to 300 mg, 600 mg and 900 mg of azithromycin per bottle. The non-medicinal ingredients include: sucrose, xanthan gum, hydroxypropylcellulose, trisodium phosphate anhydrous, colloidal anhydrous silica, aspartame, cream caramel, and titanium dioxide.

STABILITY AND STORAGE RECOMMENDATIONS

TABLETS:

Store Ava-Azithromycin, film-coated tablets, between 15 and 30ºC.

POWDER FOR ORAL SUSPENSION:

Dry powder: Store at controlled room temperature (15-30°C). Protect from light.

RECONSTITUTED SUSPENSION: Store between 5°C and 30°C. Discard unused portion after 10 days.

AVAILABILITY OF DOSAGE FORMS

250 MG TABLETS: pink, film-coated, oval-shaped, scored on the both sides, engraved "A250" on one side. These are supplied in boxes containing aluminum-backed blister strips of 6 tablets, or bottles containing 100 tablets.

POWDER FOR ORAL SUSPENSION: Ava-Azithromycin Powder for Oral Suspension, after reconstitution, contains a caramel flavoured suspension. Each bottle provides azithromycin monohydrate equivalent to: 300 mg per 15 mL (100 mg/ 5 mL); 600 mg per 15 mL (200 mg/5mL) and 900 mg per 22.5 mL (200 mg/ 5mL) azithromycin. A graduated syringe is included in the package.