Azithromycin (4513347 Canada) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

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, duration 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 AZITHROMYCIN may be initiated before results of these tests are known; once the results become available, antibiotic treatment should be adjusted accordingly.

ADULTS:

Treatment

Pharyngitis and tonsillitis:

Pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A $-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 Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Community-acquired pneumonia:

Community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Chlamydia pneumoniae 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 agalactiae.

Genitourinary tract infections:

Urethritis and cervicitis due to Neisseria gonorrhoeae or Chlamydia trachomatis. Genital ulcer disease in men due to Haemophilus 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.

Prevention of Disseminated Mycobacterium Avium Complex (MAC) Disease: AZITHROMYCIN , taken at a dose of 1200 mg weekly, alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infections (see DETAILED PHARMACOLOGY, Clinical Trials).

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 AZITHROMYCIN my be initiated before results of these tests are known; once the results become available, antibiotic treatment should be adjusted accordingly.

.

CONTRAINDICATIONS

AZITHROMYCIN (Azithromycin Monohydrate) is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, other macrolide antibacterial agents, or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

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 therapy (see CONTRAINDICATIONS). Allergic reactions may occur during and soon after treatment with AZITHROMYCIN (Azithromycin Monohydrate). 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 pseudomembraneous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembraneous 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.

Since liver is the major route of elimination for Azithromycin the use of AZITHROMYCIN (Azithromycin Monohydrate) 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).

Pronlonged cardiac repolarisation and QT interval imparting a risk of developing cardiac arrythmia and torsades de pointes can be 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 - Post marketing Experience). These include but are not limited to: one AIDS patient dosed at 750 mg to 1g 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: Animal studies have demonstrated that azithromycin crosses the placenta. Safety of Azithromycin for use in human pregnancy has not been established.

Nursing Women: There are no data on secretion in breast milk. Safety of Azithromycin for use in human lactation has not been established.

Geriatrics (>65 years of age): 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.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The majority of side effects observed in controlled clinical trials involving patients treated with azithromycin were of a mild and transient nature. Approximately 0.7% of adult patients (n=3812) from the 5-day multiple dose clinical trials discontinued azithromycin therapy because of drug related side effects. 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%.

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.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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 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: menorhagia, urinary frequency, vaginitis

Special senses: conjunctivitis

Nervous System: dizziness

Allergic: pruritis

Single 1-gram Dose Regimen:

In adult patients (n=904), side effects that occurred on the single one-gram dosing regimen of azithromycin 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

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.

Prevention of Mycobacterium Avium Complex (MAC) Disease:

Chronic therapy with azithromycin 1200 mg weekly regimen: The nature of side effects seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens.

Incidence¹ (%) of Treatment Related* Adverse Events** in HIV-Infected Patients Receiving Prophylaxis for Disseminated MAC

^* Includes those events considered possibly or probably related to study drug ^** > 2% adverse event rates for any group

¹ Reflects the occurrence of $1 event during the entire treatment period Incidence¹ (%) of Treatment Related* Adverse Events** in HIV-Infected Patients Receiving Prophylaxis for Disseminated MAC : Continued

* Includes those events considered possibly or probably related to study drug ** > 2% adverse event rates for any group

¹ Reflects the occurrence of $1 event during the entire treatment period Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In one of the studies, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients.

Oral Regimen: Adults:

The most common side effects (greater than 1%) in adult patients who received sequential IV/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%).

In adult women who received sequential 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:

Allergic: bronchospasm

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

Special Senses: taste perversion

Abnormal Hematologic and Clinical Chemistry Findings

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.

Prevention of Mycobacterium Avium complex (MAC) Disease:

In these immunocompromised patients with advanced HIV infection, it was sometimes necessary

to assess laboratory abnormalities developing on study with additional criteria if baseline values were outside the normal range.

Prophylaxis Against Disseminated MAC Abnormal Laboratory Values

^a secondary criteria also applied if baseline abnormal, as follows: Hemoglobin, 10% decrease;

Platelet, 20% decrease; WBC count, 25% decrease; Neutrophils, 50% decrease; AST (SGOT), 50% increase; ALT (SGPT), 50% increase

^b lower limit of normal

^c upper limit of normal

In a phase I drug interaction study performed in normal volunteers, 1of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (<500 cells/mm³).

Post-Market Adverse Drug Reactions

The following adverse experiences 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 WARNINGS AND PRECAUTIONS);

Gastrointestinal: Anorexia, constipation, dehydration, vomitting/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, reports of taste perversion, abnormal vision.

DRUG INTERACTIONS

Drug-Drug Interactions

Antacids

Aluminum and magnesium containing antacids (Maalox^®) reduce the peak serum levels but not the extent of azithromycin absorption. AZITHROMYCIN (Azithromycin Monohydrate) 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 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 a 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 azithromycin had not 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_0-4 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 not 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 azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucoronide 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.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Hepatic Impairment:

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change

Administration

ADULTS

Dosing in relation to FOOD:

AZITHROMYCIN Tablets can be taken with or without food.

UPPER AND LOWER RESPIRATORY INFECTIONS / SKIN AND SKIN STRUCTURE INFECTIONS:

The recommended dose of AZITHROMYCIN for individuals 16 years of age or older in the treatment of mild to moderate acute bacterial exacerbations of chronic obstructive pulmonary disease, 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 through 5 for a total dose of 1.5 grams.

GENITOURINARY INFECTIONS:

The recommended dose of AZITHROMYCIN for the treatment of genital ulcer disease due to Haemophilus ducreyi (chancroid) and non-gonococcal urethritis and cervicitis due to C. trachomatis is: a single 1 gram (1000 mg) oral dose of AZITHROMYCIN . This dose can be administered as four 250 mg tablets.

The recommended dose of AZITHROMYCIN for the treatment of urethritis and cervicitis due to Neisseria gonorrhoeae is: a single 2 gram (2000 mg) dose of AZITHROMYCIN. This dose can be administered as eight 250 mg tablets.

FOR PREVENTION OF DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX (MAC) DISEASE:

The recommended dose of AZITHROMYCIN for the prevention of disseminated Mycobacterium avium complex (MAC) disease is 1200 mg (two 600 mg tablets) taken once weekly. This dose of AZITHROMYCIN may be continued with the approved dosage regimen of rifabutin.

OVERDOSAGE

Up to 15 grams cumulative dose of Azithromycin 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

AZITHROMYCIN (Azithromycin Monohydrate), 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.

Pharmacokinetics:

Following oral administration, azithromycin is rapidly absorbed (Tmax = 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%.

Food does not affect the absorption of Azithromycin in the tablet dosage form. Azithromycin Monohydrate tablets can be taken with or without food.

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 susbsequent 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:

^a 0- 48 hr, ^b0-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.

Special Populations and Conditions

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.

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.

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).

STORAGE AND STABILITY

Store AZITHROMYCIN (Azithromycin Monohydrate) film-coated tablets at controlled room temperature (15-30°C).

DOSAGE FORMS, COMPOSITION AND PACKAGING

250 mg: Each pink, film-coated, capsular-shaped AZITHROMYCIN (Azithromycin Monohydrate) tablet, embossed “ ” on the upper face, and “AT 250 ” on the lower face, contains azithromycin monohydrate equivalent to 250 mg of azithromycin. 600 mg: Each White to off-white, film-coated, oval, biconvex AZITHROMYCIN (Azithromycin Monohydrate) tablet, with “ ” on the upper face, and “AT , 600 ” on the lower face, contains Azithromycin Monohydrate equivalent to 600 mg of azithromycin.

Composition:

AZITHROMYCIN tablets are available in 2 strengths, namely 250mg and 600 mg. Each tablet contains azithromycin monohydrate as the active (medicinal) ingredient.

The following inactive ingredients are common to all tablet strengths:

dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, sodium lauryl sulphate, magnesium stearate, Titanium dioxide, Talc, Lecithin (Soya), and Xanthum gum.

The 250 mg tablets also contain: Ponceau 4R Aluminum Lake, Carmoisine (Azorubine) Aluminum Lake, and Quinoline Yellow Lake.

Packaging:

250 mg: Blister strips of 6 tablets and HDPE bottles of 30s and 100s.

600 mg: Blister strips of 6 tablets and HDPE bottles of 30s and 100s.

O

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CH₃

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H₃C

H₃C

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.H2O PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Azithromycin Monohydrate

Chemical Name: 9-deoxo-9"-aza-9"-methyl-9"-homoerythromycin A monohydrate

Molecular Formula: C₃₈H₇₂N₂O₁₂ .1H₂O

Molecular Mass: 767.0 (monohydrate)

749.0 (anhydrous)

Structural formula:

Azithromycin monohydrate

Physicochemical properties: Azithromycin Monohydrate is a white to off-white crystalline powder. It’s aqueous solubility at 22.4°C is 0.088 mg/mL.

pKa: 7.7

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, single-dose, cross-over comparative bioavailability study of AZITHROMYCIN (Azithromycin Monohydrate) tablets 600 mg and Zithromax^™ 600 mg tablets (Pfizer Canada Inc.) has been performed in healthy male volunteers in the fasting state.

Table of the Comparative Bioavailability Data

Azithromycin

(1 x 600 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV%)

^‡ Zithromax^TM is manufactured by Pfizer Canada Inc. and was purchased in Canada. * expressed as arithmetic mean (CV%) only.

^# Indicate % Confidence Interval (i.e., 90% or 95%) in the column heading and list for the AUC_T, AUC_I and

C_MAX (if required).

From the perspective of evaluating clinical trials because of the extended half-life of azithromycin, days 11-14 (10-13 days after completion of the one-day regimen, 8-11 days after completion of the three-day regimen or 6-9 days after completion of the five-day regimen) were considered on-therapy evaluations and are provided for clinical guidance. Day 21- 30 evaluations were considered the primary test of cure endpoint. For patients with community-acquired pneumonia, Days 15-19 were considered as on-therapy evaluations. Days 28-42 were the cure endpoint.

Clinical Trials: In patients with advanced HIV infection for the prevention of disseminated Mycobacterium avium complex (MAC) disease (see INDICATIONS AND CLINICAL USE).

Two randomized, double-blind clinical trials were performed in patients with CD4 counts <100 cells/:L. The first study compared azithromycin (1200 mg once weekly) to placebo and enrolled

182 patients with a mean CD4 count of 35 cells/:L. The second study randomized 723 patients to either azithromycin (1200 mg once weekly), rifabutin (300 mg daily) or the combination of both. The mean CD4 count was 51 cells/:L. Endpoints included disseminated MAC disease, the incidence of clinically significant disseminated MAC disease and discontinuations from therapy for drug-related side effects.

^____ Azith -- ----- Rif

........ Azith/Rif

MAC Bacteremia

In the first study, in the intent-to-treat analysis comparing azithromycin to placebo, patientsrandomized to azithromycin were one-half as likely to develop MAC as those who received placebo (p= 0.004). The one year cumulative incidence rate of disseminated MAC disease was 8.25% on azithromycin and 20.22% on placebo.

In the second study, in the intent-to-treat analysis comparing azithromycin, rifabutin and the combination of azithromycin/rifabutin, the risk of developing MAC bacteremia for patients assigned to azithromycin was also reduced by one-half relative to rifabutin (p=.005). Patients on the combination of azithromycin and rifabutin experienced a risk reduction of approximately two-thirds compared to rifabutin alone (p<0.001). The one year cumulative incidence rate of MAC infection was 7.62% on azithromycin, 15.25% on rifabutin and 2.75% on the combination.

In the placebo-controlled first study, all MAC isolates recovered within 30 days of the last dose of drug from patients randomized to azithromycin were sensitive to azithromycin. In the second study, 2of 23 (8.7%) isolates received from patients randomized to azithromycin were resistant to azithromycin while none of the isolates received from patients randomized to rifabutin were resistant to azithromycin (p=0.14). None of the isolates recovered from patients randomized to the combination of azithromycin and rifabutin were resistant to azithromycin.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients in the groups randomized to either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss and anemia.

Discontinuations from Therapy for Drug-Related Side Effects

In the first study, discontinuations from drug-related toxicity occurred in 8.2% of subjects treated

with azithromycin and 2.3% of those given placebo (p=0.121). In the second study, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p=0.026) or rifabutin alone (15.9%).

DETAILED PHARMACOLOGY

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%.

Adults

Following administration of a 500 mg oral dose, the maximum serum concentration (Cmax) is 0.4 µg/mL and is attained 2-3 hours after dosing with areas under the curve of 2.6 µg.hr/mL (AUC_0-24) and 3.7 µg.hr/mL (AUC_0-48) and trough levels of 0.05 µg/mL. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500 mg I.V. 3-hour infusion: C_max 1.08 µg/mL, trough level 0.06 µg/mL, and AUC₂₄ 5.0 µg.hr/mL. Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.

Also refer to tabulated pharmacokinetic data reported in adults under ACTIONS AND CLINICAL PHARMACOLOGY, section. 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.

The pharmacokinetic parameters of azithromycin in plasma, after a loading dose of 500 mg on day 1 followed by 250 mg q.d. on days 2 through 5 in healthy young adults (age 18-40 years old) are presented in the following table:

Pharmacokinetic Parameters (Mean) in Adult Subjects (Total n=12) on Days 1 and 5*

* 2 x 250 mg on Day 1 followed by one 250 mg on days 2 through 5 In this study, there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With this regimen, C_min and C_max remained essentially unchanged from day 2 through day 5 of therapy. However, without s loading dose, azithromycin C_min levels required 5 to 7 days to reach steady-state.

In a two-way crossover study, 12 adult normal volunteers (6 males; 6 females) received 1500 mg of azithromycin, administered in single daily doses over 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2-5) or 3 days (500 mg per day). Mean peak serum concentrations were similar on day 1 for both regimens and slightly higher on days 2 and 3 for the 3-day regimen, suggesting that there is minimal serum accumulation of azithromycin on days 2 and 3 of the 3-day regimen.

Mean AUC_0-4 for both regimens were similar, with a ratio of AUC_0-4 (3-day) / AUC_0-4 (5-day) of 105% (90% CI= 93, 120). Serum concentrations of azithromycin declined in a polyphasic pattern

resulting in average terminal half-life of 68.6 hours for the 3-day regimen and about 66 hours for the 5-day regimen.

Median azithromycin exposure (AUC_0-288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following either the 5-day or 3-day regimen was more than 1000-fold and 800-fold greater than in serum, respectively. Administration of the same total dose with either the 5-day or 3-day regimen may be expected to provide comparable concentrations of azithromycin with MN and PMN leukocytes.

The table below compares pharmacokinetic parameters following single oral doses of 500 mg azithromycin with those obtained after a single 500 mg I.V. 3-hour infusion. Pharmacokinetic parameters in adults after oral and intravenous administration of 500 mg azithromycin

Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval. Although tissue levels have not been obtained following intravenous infusions of azithromycin, these data suggest that they would be substantially greater than those observed following oral administration.

After oral administration, serum concentrations of azithromycin decline in a polyphasic pattern, resulting in an average terminal half-life of 68 hours.

The high values for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. The tissue (or fluid) to plasma concentration ratios for key sites of infection are shown in the following table:

* Samples were obtained 2-24 hours after the first dose ** Dosing regimen of 2 doses of 250 mg each, separated by 12 hours *** Sample was obtained 19 hours after a single 500 mg dose The extensive tissue distribution is confirmed by examination of other tissues (prostate; ovary, uterus and salpinx, stomach; liver and gallbladder), in which azithromycin is present in concentrations of 2 :g/g tissue or greater. However, only very low concentrations are noted in cerebrospinal fluid (less than 0.01 :g/mL) of noninflamed meninges. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy.

The extent of absorption is unaffected by co-administration with antacid; however, the Cmax is reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption. There is no evidence of any pharmacokinetic interaction when

azithromycin and theophylline are administered to healthy volunteers.

Azithromycin did not affect the prothrombin time response to a single dose of warfarin (15 mg). However, prudent medical practice dictates careful monitoring of prothrombin time in all patients.

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 :g/mL to 7% at 2 :g/mL. These values are not likely to be high enough to influence the protein binding of other drugs or to cause significant protein binding interactions with other drugs.

Following a five-day dosing regimen, human bile contains concentrations of azithromycin much greater (approximately 200 g/mL) than those in serum (<0.1 g/mL), indicating that biliary excretion of azithromycin is a major route of elimination. The major portion of the drug-related material in bile is unchanged drug. Approximately 6% of the administered dose appears in urine.

In patients with mild to moderate hepatic impairment, there is no evidence of marked change in serum pharmacokinetics of azithromycin compared to those with normal hepatic function. In these patients urinary recovery of azithromycin appears to increase.

Following oral administration of a single azithromycin 1200 mg dose (two 600mg tablets), the mean maximum concentration of azithromycin in peripheral leukocytes was 140 ng/mL. Concentrations remained above 32 ng/mL for approximately 60 hr.

The absolute bioavailability of two 600 mg azithromycin tablets was 34%. Administration of two

600 mg tablets with food increased C_max by 31% while the extent of absorption (AUC) was unchanged.

MICROBIOLOGY

The in vitro susceptibility of clinical isolates to azithromycin is presented in Table 1 (gram-positive bacteria), Table 2 (fastidious gram-negative organisms), Table 3 (aerobic gram-negative species), Table 4 (anaerobic organisms), Table 5 (mycoplasmataceae and intracellular pathogens) and Table 6 (Streptococcus pneumoniae). For susceptibility testing both agar and broth dilution methods were used. In the agar dilution method, each inoculum spot contained approximately 2x10⁴ cells/strain. In the broth dilution method, final inoculum size was $1x10⁶ colony-forming units per mL. Chlamydia organisms were tested in McCoy monolayers. Beta-lactamase production has not been shown to produce an effect on the activity of azithromycin.

TABLE 1

In vitro activity of azithromycin against clinical isolates of gram-positive bacteria

NA= not available

TABLE 2

Susceptibility of fastidious gram-negative organisms to azithromycin

NA = not available TABLE 3

Susceptibility of Enterobacteriaceae and other aerobic gram-negative species to azithromycin

NA = not available TABLE 3 : Continued

Susceptibility of Enterobacteriaceae and other aerobic gram-negative species to azithromycin

NA = not available TABLE 4

In vitro activity of azithromycin against anaerobic organisms

NA = not available TABLE 5

Activity of azithromycin against Mycoplasmataceae and intracellular pathogens

NA = not available TABLE 6

Published azithromycin susceptibility results for Streptococcus pneumoniae

^a Abbreviations: BHI, Brain Heart Infusion; MHA, Mueller Hinton Agar; SMHB, supplemented Mueller Hinton Broth.

^b Erythromycin resistant strains

These data suggest that there is cross-resistance between erythromycin and azithromycin. Diffusion Techniques: Measurement of zone-inhibition diameters by the agar diffusion method of Kirby and Bauer is the recommended means of susceptibility testing. A standard 15 :g disc is used. Results of laboratory testing should be interpreted using the following criteria (NCCLS Performance Standards for Antimicrobial Susceptibility Testing, Volume 18, No. 1, January 1998):

* These zone diameter standards apply only to tests with Haemophilus spp. using Haemophilus Test Medium (HTM).

* These zone diameters for streptococci apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO₂.

No interpretative criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested.

A report of “Susceptible” indicates that the pathogen is likely to respond to monotherapy with azithromycin. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the organism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretations. A report of “Resistant” indicates that achievable drug concentrations are unlikely to be inhibitory and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 15 :g azithromycin disk should give the following diameter (NCCLS Performance Standards for Antimicrobial Susceptibility Testing, Volume 18, No. 1, January 1998):

Dilution Techniques: Broth and agar dilution methods, such as those recommended by the NCCLS, may be used to determine the minimum inhibitory concentrations (MIC) of azithromycin, using the following criteria (NCCLS Performance Standards for Antimicrobial Susceptibility Testing, Volume 18, No.1, January 1998):

* These interpretative standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium.

The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a CO₂ atmosphere will result in lowering of media pH (7.2 to 6.6, 18h in 10% CO₂) and a reduction in potency of azithromycin. Thus, the initial pH of the growth medium should be physiological (7.2-7.4) and the CO₂ content of the incubation atmosphere should be as low as is practical. Azithromycin can be solubilized for in vitro testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water.

As with standard diffusion methods, dilution methods require the use of laboratory control organisms. Standard azithromycin powder should provide the following MIC values (NCCLS Performance Standards for Antimicrobial Susceptibility Testing, Volume 18, No. 1, January 1998):

TOXICOLOGY

Acute Toxicity: Mice and Rats

* NA = not available

Adult animals (Mice and Rats)

Most mortality occurred within 1 to 2 hours and generally within 48 hours of dosing. At higher doses in mice, symptomatology, included clonic convulsive activity, loss of righting reflex, gasping, and blanching prior to death.

Gross necropsy of mice or rats which died following intraperitoneal doses revealed yellowish or clear fluid in the pleural and peritoneal cavities. At necropsy on day 14 there were no gross pathological changes in either species aside from a few liver adhesions to the diaphragm. Neonatal animals (Rats)

No deaths or remarkable clinical signs were observed in any animal during the 14-day observation period. All animals gained weight during the trial. At sacrifice on day 15, no remarkable gross findings were observed in any surviving rat.

Subacute Toxicity

Phospholipidosis has been observed in animals administered high doses of azithromycin. This effect is reversible after cessation of azithromycin treatment in animals. Despite light- and electron- microscopic correlates of phospholipidosis (myeloid figures and intracytoplasmic vacuoles) in many organs, only in dogs receiving 100 mg/kg/day for at least 2 months have kidney, liver, and gallbladder toxicity been seen. This dose in dogs results in tissue levels greater than 5000 mg/g. Minimal increases in serum transaminase levels in rats and dogs at 20 mg/kg/day and above have also been seen, but are consistent with findings previously reported for erythromycin. Special attention has been given to the effects of phospholipidosis in the retina, including studies of azithromycin, 30 and 100 mg/kg/day for 6 and 2 months, respectively, in dogs. No evidence was elicited of deleterious effects of azithromycin on vision, pupillary reflex or retinal vasculature. The detection of phospholipidosis in the choroid plexus and dorsal root ganglion was not associated with degenerative or functional changes. Subacute and Chronic Toxicity

Reproductive Studies

Fetotoxicity Teratology

Neonatal Studies

Carcinogenicity

Long-term toxicology studies to assess the carcinogenicity potential have not been conducted.

Genetic Toxicology

Azithromycin was examined in several genetic toxicology assays for induction of gene mutations

in microbial and mammalian cells and for chromosomal mutations in vivo and in vitro. No evidence of genotoxic activity was observed in any of the following assays:

Microbial Assay: Tests were conducted on strains TA 1535, TA 1537, TA 98 and TA 100 of Salmonella typhimurium at concentrations up to 2 :g/plate (higher concentrations cause bacterial growth inhibition) in the presence and absence of Aroclor-stimulated rat or mouse liver microsomal enzymes. Additional tests were performed using the same strains of Salmonella spp. and urine from mice treated orally with up to 200 mg/kg of azithromycin.

Mammalian Cell Gene Mutation Assay: The L5178Y Mouse Lymphoma Assay for gene mutations at the thymidine kinase locus was conducted at concentrations of 36-360 :g/mL to cytotoxicity in the presence and absence of rat liver microsomal enzymes.

In Vitro Cytogenetics Assay: The clastogenic activity of azithromycin was evaluated in human lymphocytes in vitro exposed up to toxic concentrations of 40 :g/mL in the presence and 7.5 :g/mL in the absence of rat liver microsomal enzymes.

In Vivo Cytogenetics Assay: Azithromycin was examined for clastogenic activity in the bone marrow cells of male and female CD-1 mice treated orally at 200 mg/kg, and sacrificed at 6, 24, or 48 hours post-treatment.

Antigenicity Studies

Azithromycin was tested for the induction of a systemic anaphylaxis reaction in guinea pigs and in rabbits. Azithromycin did not have antigenic potential under the conditions used in the studies.

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