Riva-Azithromycin Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 5

2 CONTRAINDICATIONS ................................................................................................. 5

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations ............................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 6

4.5 Missed Dose ........................................................................................................... 6

5 OVERDOSAGE ............................................................................................................. 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 7

7 WARNINGS AND PRECAUTIONS .................................................................................. 8

7.1 Special Populations .............................................................................................. 11

7.1.1 Pregnant Women .............................................................................................. 11

7.1.2 Breast-feeding ................................................................................................... 11

7.1.4 Geriatrics ........................................................................................................... 12

8 ADVERSE REACTIONS................................................................................................ 12

8.1 Adverse Reaction Overview ................................................................................ 12

8.2 Clinical Trial Adverse Reactions ........................................................................... 12

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................. 15

8.5 Post-Market Adverse Reactions ........................................................................... 16

9 DRUG INTERACTIONS ............................................................................................... 17

9.2 Drug Interactions Overview .................................................................................. 17

9.4 Drug-Drug Interactions ......................................................................................... 18

9.5 Drug-Food Interactions ......................................................................................... 23

9.6 Drug-Herb Interactions ......................................................................................... 23

9.7 Drug-Laboratory Test Interactions........................................................................ 23

10 CLINICAL PHARMACOLOGY ....................................................................................... 23

10.1 Mechanism of Action ............................................................................................ 23

10.2 Pharmacodynamics ............................................................................................... 23

10.3 Pharmacokinetics .................................................................................................. 24

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 25

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 25

PART II: SCIENTIFIC INFORMATION ...................................................................................... 26

13 PHARMACEUTICAL INFORMATION ........................................................................... 26

14 CLINICAL TRIALS ....................................................................................................... 27

14.2 Comparative Bioavailability Studies ..................................................................... 27

15 MICROBIOLOGY ....................................................................................................... 32

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 35

17 SUPPORTING PRODUCT MONOGRAPHS .................................................................... 54

PATIENT MEDICATION INFORMATION ................................................................................. 55

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

RIVA-AZITHROMYCIN for Oral Administration

RIVA-AZITHROMYCIN (azithromycin dihydrate tablets) for oral administration 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 4 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 RIVA-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 dihydrate is often effective in the eradication of susceptible strains of streptococci from the oropharynx. However, data establishing the efficacy of azithromycin dihydrate 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 nosocomial 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:

RIVA-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 14 CLINICAL TRIALS).

1.2 Geriatrics

Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness. However, elderly patients may be more susceptible to development of torsade de pointes arrhythmias. (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular; 7.1.4 Geriatrics; 10 CLINICAL PHARMACOLOGY).

2 CONTRAINDICATIONS

RIVA-AZITHROMYCIN is contraindicated:

• in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin
• in those with a hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibacterial agent, or to any ingredient in the formulation or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Azithromycin dihydrate immediate-release oral formulations are not bioequivalent and are not interchangeable with azithromycin sustained release due to a different pharmacokinetic profile.

Hepatic Impairment:

No dose adjustment of oral RIVA-AZITHROMYCIN preparations is recommended for patients with mild to moderate hepatic impairment. Azithromycin has not been studied in patients with severe hepatic impairment. Since the liver is the principal route of elimination for azithromycin, the use of oral azithromycin dihydrate preparations should be undertaken with caution in patients with impaired hepatic function (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY

Renal Impairment:

No dosage adjustment of oral RIVA-AZITHROMYCIN preparations is recommended for subjects with GFR 10-80 mL/min. The mean AUC_0-120 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 GFR <10 mL/min. No studies have been conducted in patients requiring hemodialysis (see 7 WARNINGS AND PRECAUTIONS and 10 CLINICAL PHARMACOLOGY).

4.2 Recommended Dose and Dosage Adjustment

RIVA-AZITHROMYCIN for ORAL THERAPY

ADULTS

DOSING in relation to FOOD:

TABLETS: RIVA-AZITHROMYCIN Tablets can be taken with or without food.

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

The recommended dose of RIVA-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 RIVA-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 through 5 for a total dose of 1.5 grams.

GENITOURINARY INFECTIONS:

The recommended dose of RIVA-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 RIVA-AZITHROMYCIN. This dose can be administered as four 250 mg tablets.

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

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

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

4.5 Missed Dose

In case of missed dose, patients should not double the next dose.

5 OVERDOSAGE

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.

Ototoxicity and gastrointestinal adverse events may occur with an overdose of azithromycin.

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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition, and Packaging

RIVA-AZITHROMYCIN 250 mg tablets: are pink colored, modified capsular shaped, biconvex, film coated tablet debossed with “A 250” on one side and other side plain contains azithromycin dihydrate equivalent to 250 mg of azithromycin.

The tablets are packaged in white plastic (high density polyethylene) bottles of 100; blisters cartons of 6 tablets.

RIVA-AZITHROMYCIN 600 mg tablets: are white colored, modified capsular shaped, biconvex, film coated tablet debossed with “A 600” on one side and other side plain containing azithromycin dihydrate equivalent to 600 mg azithromycin.

The tablets are packaged in white plastic (high density polyethylene) bottles of 30.

7 WARNINGS AND PRECAUTIONS

General

• Azithromycin and ergot derivatives should not be co-administered due to the possibility that ergot toxicity may be precipitated by macrolide antibiotics. Acute ergot toxicity is characterized by severe peripheral vasospasm, including ischemia of the extremities, along with dysesthesia and possible central nervous system effects. The use of azithromycin with other drugs may lead to drug-drug interactions. For established or potential drug interactions, see 9 DRUG INTERACTIONS section of the product monograph.
• As with any antibacterial preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
• Intramuscular use of azithromycin is not recommended; extravasation of drug into the tissues may cause tissue injury.

Carcinogenesis and Mutagenesis

Long term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no genotoxic or mutagenic potential in standard laboratory tests (see 16 NON- CLINICAL TOXICOLOGY).

Cardiovascular

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including azithromycin (see 8 ADVERSE REACTIONS). Prescribers should consider the risk of QT prolongation which can lead to fatal events when weighing the risks and benefits of azithromycin. Risk factors for torsade de pointes include patients:

• With a history of torsade de pointes
• With congenital or documented QT prolongation
• Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of classes IA and III; antipsychotic agents; antidepressants; and fluoroquinolones.
• With electrolyte disturbance, particularly in cases of hypokalemia and hypomagnesemia
• With clinically relevant bradycardia, cardiac arrhythmia or cardiac insufficiency
• Elderly may be more susceptible to drug-associated effects on the QT interval
• Exposed to higher plasma levels of azithromycin (e.g. receiving intravenous azithromycin, hepatobiliary impaired)

There is information that 'QT Related Adverse Events' may occur in some patients receiving azithromycin. There have been spontaneous reports from post-marketing experience of prolonged QT interval and torsade de pointes (see 8.5 Post-Market Adverse Reactions). These include but are not limited to: one AIDS patient dosed at 750 mg to 1 g daily experienced prolonged QT interval and torsade de pointes; a patient with previous history of arrhythmias who experienced torsade 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 (see 10 CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).

Endocrine and Metabolism

Lysosomal lipid storage diseases

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 RIVA-AZITHROMYCIN in these patients is not recommended.

Saccharide Intolerance

• Due to the lactose content in the tablet coating, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take the tablet formulation.

Gastrointestinal

A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Azithromycin was administered to a limited number of subjects with GFR<10 mL/min.

Clostridioides difficile associated disease

Clostridioides difficile associated disease (CDAD) has been reported with use of many antibacterial agents including azithromycin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agents. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridioides difficile. Clostridioides difficile produces toxins A and B which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridioides difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridioides difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 8 ADVERSE REACTIONS).

Hematologic

Severe neutropenia (WBC < 1000/mm³) may adversely affect the distribution of azithromycin and its transport to the site of infection. Antibacterials with proven efficacy in this population should be used, as outlined by the relevant guidelines for treatment of patients with severe neutropenia. Efficacy and safety of azithromycin have not been studied in patients with severe neutropenia.

Hepatic/Biliary/Pancreatic

Since the liver is the principal route of elimination for azithromycin, the use of oral RIVA-AZITHROMYCIN preparations should be undertaken with caution in patients with impaired hepatic function. Azithromycin has not been studied in patients with severe hepatic impairment (see 10 CLINICAL PHARMACOLOGY).

Hepatotoxicity

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Rare cases of acute hepatic necrosis requiring liver transplant or causing death have been reported in patients following treatment with oral azithromycin. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur (see 8 ADVERSE REACTIONS).

Immune

Allergic reactions may occur during and soon after treatment with azithromycin dihydrate. 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.

Monitoring and Laboratory Tests

Monitoring of QT/QTc intervals during treatment with RIVA-AZITHROMYCIN may be considered by the physician as appropriate.

Musculoskeletal

Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. The use of azithromycin in patients with a known history of myasthenia gravis is not recommended.

Renal

The safety, efficacy and pharmacokinetics of azithromycin dihydrate in patients with renal impairment have not been established. No dose adjustment is recommended for patients with GFR 10-80 mL/min. Caution should be exercised when azithromycin dihydrate is administered to patients with GFR <10 mL/min. This precaution is based on a clinical study of azithromycin immediate-release tablets, in which patients with GFR <10 mL/min showed a significant (61%) increase in mean Cmax and a significant (35%) increase in systemic exposure to azithromycin and experienced a high incidence of gastrointestinal adverse events (8 of 19 clinical study subjects). Patients with GFR 10-80 mL/min showed only slightly increased serum azithromycin levels compared to patients with normal renal function.

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

Reproductive Health: Female and Male Potential

• Fertility

  There are no adequate and well-controlled studies in humans. In fertility studies conducted in the rat, reduced pregnancy rates were noted following administration of azithromycin. The predictive value of these data to the response in humans has not been established (see 16 NON-CLINICAL TOXICOLOGY).

Sensitivity/Resistance

Prescribing azithromycin dihydrate in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Skin

Serious allergic reactions, including angioedema, anaphylaxis, and dermatological reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermolysis, toxic epidermal necrolysis (TEN) and Drug Reaction with Eosinophilia and Systemic symptoms (DRESS) have been reported rarely (with rare reports of fatalities), in patients on azithromycin dihydrate therapy (see 2 CONTRAINDICATIONS).

7.1 Special Populations

7.1.1 Pregnant Women

Azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any potential risk to the fetus.

There is a large amount of data from observational studies performed in several countries on exposure to azithromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period. While most studies do not suggest an association with adverse fetal effects such as major congenital malformations or cardiovascular malformations, there is limited epidemiological evidence of an increased risk of miscarriage following azithromycin exposure in early pregnancy.

In animal reproduction studies in mice and rats, at azithromycin doses up to 200 mg/kg/day (moderately maternally toxic), effects were noted in the rat at 200 mg/kg/day, during the prenatal development period (delayed ossification) and during the postnatal development period (decreased viability, delayed developmental landmarks, differences in performance of learning task). The 200 mg/kg/day dose in mice and rats, is approximately 0.5-fold and 1-fold, respectively, the single adult oral dose of 2 g, based on mg/m² (body surface area). Pharmacokinetic data from the 200 mg/kg/day dose level in these studies showed that azithromycin crossed the placenta and distributed to fetal tissue at 5 to 9-fold the maternal plasma C_max of 2 ug/mL (see 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

RIVA-AZITHROMYCIN should not be used in the treatment of nursing women unless the expected benefit to the mother outweighs any potential risk to the infant. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Because azithromycin may accumulate in breast milk over time with continued RIVA-AZITHROMYCIN therapy, if the lactating mother is treated with RIVA-AZITHROMYCIN, the breast milk should be expressed and discarded during treatment.

Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. However, the safety of azithromycin has not been studied in infants less than 6 months of age.

7.1.4 Geriatrics

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). However, elderly patients may be more susceptible to development of torsade de pointes arrhythmias.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

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 dihydrate 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 dihydrate. Potentially serious treatment-related side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

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%), nausea (3-4%), abdominal pain (2-3%) and vomiting (1%).

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

Allergic: pruritus

Cardiovascular: hypertension

Gastrointestinal: dry mouth, esophagitis, gastroenteritis, rectal hemorrhage, cholestatic jaundice

Genitourinary: menorrhagia, urinary frequency, vaginitis

Nervous system: dizziness

Special senses: conjunctivitis

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 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.

Prevention of Mycobacterium Avium Complex (MAC) Disease:

Chronic therapy with azithromycin dihydrate 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.

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.

Intravenous/Oral Regimen: Adults

The most common side effects (greater than 1%) in adult patients who received sequential I.V./oral azithromycin dihydrate 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 dihydrate 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

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

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

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, 1 of 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).

8.5 Post-Market Adverse 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.

In addition, because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency is not always possible.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Drugs that cause QT prolongation

Caution is warranted when azithromycin is administered to a patient with a history of a significant cardiac repolarization disorder or who is taking other medicinal products that cause a prolonged QT interval (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 8.5 Post-Market Adverse Reactions).

P-glycoprotein substrates

Concomitant administration of azithromycin with P-glycoprotein substrates may result in increased serum levels of P-glycoprotein substrates. Concomitant administration of P-glycoprotein inhibitors with azithromycin sustained-release form had minimal effect on the pharmacokinetics of azithromycin.

Hepatic cytochrome P450

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

9.4 Drug-Drug Interactions

Established or Potential Drug-Drug Interactions

Legend: CT = Clinical Trial

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 post marketing experience. Until further data are developed regarding drug interactions, when RIVA-AZITHROMYCIN and these drugs are used concomitantly, careful monitoring of patients is advised both during and for a short period following therapy:

Antihistamines

Prolongation of QT intervals, palpitations or cardiac arrhythmias have been reported with concomitant administration of azithromycin and astemizole or terfenadine.

Cisapride, Hexobarbital, Phenytoin

Increased serum levels of hexobarbital, cisapride or phenytoin have been reported.

Digoxin and colchicine / P-glycoprotein substrates

Concomitant administration of some macrolide antibiotics with P-glycoprotein substrates, including digoxin and colchicine, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations should be considered. Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary.

Disopyramide: Azithromycin may increase the pharmacologic effect of disopyramide.

Ergot (ergotamine or dihydroergotamine)

Azithromycin and ergot derivatives should not be co-administered due to the possibility that ergot toxicity may be precipitated by some macrolide antibiotics. Acute ergot toxicity is characterized by severe peripheral vasospasm including ischemia of the extremities, along with dysesthesia and possible central nervous system effects.

Gentamicin

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.

Triazolam

Azithromycin may decrease the clearance of triazolam and increase the pharmacologic effect of triazolam.

9.5 Drug-Food Interactions

Azithromycin tablets can be taken with or without food.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Azithromycin dihydrate, a macrolide antibiotic of the azalide subclass, exerts its antibacterial action by binding to the 23S rRNA of the 50s ribosomal subunits of susceptible bacteria. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit.

10.2 Pharmacodynamics

Cardiac Electrophysiology:

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial. A total of 119 healthy subjects were enrolled (mean age of 35.5 years; range 18-55 years), of which 116 subjects (97 males) completed the study and were included in the analysis. Subjects were randomized to one of 5 treatments and received orally once daily for 3 days: placebo, chloroquine 600 mg base only, or chloroquine 600 mg base in combination with azithromycin 500 mg, 1000 mg, and 1500 mg. On Day 3, the azithromycin mean (%CV) plasma Cmax values for the 500, 1000 and 1500 mg azithromycin dose regimens were 0.536 (33), 0.957 (31), and 1.54 (28) µg/mL, respectively. Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the day 3 maximum mean (90% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

10.3 Pharmacokinetics

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.

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.

In adults, the following pharmacokinetic data have been reported:

^a 0-48 hr; ^b 0-last

Absorption:

Following oral administration, azithromycin is rapidly absorbed (T_max = 2-3 hours) and distributed widely throughout the body.

The absolute bioavailability is approximately 37%.

When azithromycin suspension was administered with food to 28 adult healthy male subjects, the rate of absorption (Cmax) 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 can be taken with or without food.

Distribution:

The serum protein binding of azithromycin is concentration dependent, decreasing from 51% at 0.02 μg/mL to 7% at 2.0 μg/mL. Following oral administration, azithromycin is widely distributed throughout the body with a steady-state apparent volume of distribution of 31.1 L/kg.

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 long tissue half-life and large volume of distribution result from intracytoplasmic uptake and storage in lysosomal phospholipid complexes.

Metabolism:

The majority of systemically available azithromycin is excreted unchanged in the bile. Metabolites of azithromycin were identified in bile but have not been studied further.

Elimination:

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.

Sex:

There are no significant differences in the disposition of immediate-release azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.

Hepatic Insufficiency:

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. Azithromycin has not been studied in patients with severe hepatic impairment.

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 GFR 10 to 80 mL/min compared to subjects with GFR >80 mL/min. The mean C_max and AUC_0-120 increased 61% and 35%, respectively in subjects with GFR <10 mL/min compared to subjects with GFR >80 mL/min.

11 STORAGE, STABILITY AND DISPOSAL

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

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions for this drug product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: azithromycin dihydrate

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

Molecular formula and molecular mass: C₃₈H₇₂N₂0₁₂ .2H₂O (785.02)

Structural formula:

Physicochemical properties: Azithromycin dihydrate is a white to almost white powder.

The aqueous solubility at pH 7.4 at 37°C is 39 mg/mL.

The powder is non-hygroscopic.

pK_a: 8.1 and 8.8

14 CLINICAL TRIALS

14.2 Comparative Bioavailability Studies

A single oral dose (1 x 600 mg), randomized, double blinded, two treatment, two period, two sequence, two-way crossover, comparative bioavailability study of RIVA-AZITHROMYCIN (Laboratoire Riva Inc.) and ZITHROMAX (Pfizer Canada Inc.) was conducted in 29 healthy adult male subjects under fasting conditions. A summary of the bioavailability data from the 29 subjects that were included in the statistical analysis is presented in the table below.

Summary Table of the Comparative Bioavailability Data

¹ RIVA-AZITHROMYCIN (azithromycin dihydrate) 600 mg tablets (Laboratoire Riva Inc.).

² ZITHROMAX (azithromycin dihydrate) 600 mg tablets (Pfizer Canada Inc., Canada).

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

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.

Pediatric Patients:

Otitis Media:

Efficacy using azithromycin 30 mg/kg given over 5 days

Protocol 1

In a double-blind, controlled clinical study of acute otitis media performed in North America, azithromycin (10 mg/kg on day 1 followed by 5 mg/kg on days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the day 11 visit was 88% for azithromycin and 88% for the control agent. For the 528 patients who were evaluated at the day 30 visit, the clinical success rate was 76% for azithromycin and 76% for the control agent.

Protocol 2

In a non-comparative clinical and microbiologic trial performed in North America and in which significant numbers of β-lactamase producing organisms were identified (35%), the combined clinical success rate (i.e., cure plus improvement) was 84% at the day 11 visit (n=131) and 70% at the day 30 visit (n=122).

Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group:

From the perspective of evaluating clinical trials in patients using the 3 day or 1 day accelerated regimen of azithromycin, the analysis of efficacy was based on a Modified Intent to Treat population with efficacy assessments at approximately Day 11-16 and Day 28-32. Since peak age incidence for acute otitis media is 6-18 months of age, stratified data is provided for clinical guidance in this age group.

Efficacy using azithromycin 30 mg/kg given over 3 days

Protocol 3

In a double-blind, controlled, randomized clinical study of acute otitis media in North American children from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each child received active drug and placebo matched for the comparator. For the 366 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the day 12 visit was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the day 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent.

Efficacy using azithromycin 30 mg/kg given as a single dose

Protocol 4

In a double-blind, controlled, randomized clinical study of acute otitis media in North American children from 6 months to 12 years of age, azithromycin (given at 30mg/kg as a single dose on day 1) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each child received active drug, and placebo matched for the comparator. For the 321 subjects who were evaluated at Day 12-16, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Day 28-32, the clinical success rate was 75% for both azithromycin and the comparator.

Protocol 5

In a non-comparative clinical and microbiological trial enrolling 70% North American children and 30% South American children, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on day 1). For the 240 evaluable patients, the clinical success rate (i.e., cure plus improvement) at day 10 was 89% and for the 242 patients evaluable at day 24-28, the clinical success rate (cure) was 85%. Of the 76 S. pneumoniae isolates, 16% exhibited resistance to azithromycin at baseline. No bacterial eradication data is available for the azithromycin 3-day regimen.

Pharyngitis and Tonsillitis:

Efficacy using azithromycin 60 mg/kg over 5 days

In three double-blind North American controlled studies, azithromycin (12 mg/kg once a day for 5 days) was compared to penicillin V (250 mg three times a day for 10 days) in the treatment of pharyngitis due to documented group A β-hemolytic streptococci (GAβHS or S. pyogenes). Azithromycin was clinically and microbiologically statistically superior to penicillin at day 14 and day 30 with the following clinical success (i.e., cure and improvement) and bacteriologic efficacy rates (for the combined evaluable patients with documented GaβHS):

3 Combined Streptococcal Pharyngitis

Studies 5-Day Dosing Regimen

Azithromycin vs. Penicillin V EFFICACY RESULTS

Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to azithromycin following therapy.

Adult Patients

Acute Bacterial Exacerbations of Chronic Bronchitis:

Efficacy using azithromycin 500 mg over 3 days

In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB) in 404 adult patients, azithromycin (500 mg once daily for 3 days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Day 21-

1. 24. For the 377 patients analyzed in the MITT analysis at the Day 21-24 visit, the clinical cure rate for 3 days of azithromycin was 87% (162/186) compared to 85% (162/191) for 10 days of clarithromycin (95% CI for azithromycin-clarithromycin cure rate = -5.3, 9.8).

The following outcomes were the clinical cure rates at the Day 21-24 visit for the bacteriologically evaluable patients by pathogen:

In patients with advanced HIV infection for the prevention of disseminated

Mycobacterium avium complex (MAC) disease (see 1 INDICATIONS):

Two randomized, double-blind clinical trials were performed in patients with CD4 counts <100 cells/µL. The first study compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/µL. 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/µL. Endpoints included disseminated MAC disease, the incidence of clinically significant disseminated MAC disease and discontinuations from therapy for drug-related side effects.

MAC Bacteremia:

In the first study, in the intent-to-treat analysis comparing azithromycin to placebo, patients randomized 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.

Azithromycin dihydrate

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, 2 of 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 for 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%).

15 MICROBIOLOGY

Mechanism of Resistance:

The two most frequently encountered mechanisms of resistance to macrolides, including azithromycin, are target modification (most often by methylation of 23S rRNA) and active efflux. The occurrence of these resistance mechanisms varies from species to species, and, within a species, the frequency of resistance varies by geographical location.

Spectrum of Activity:

Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in 1 INDICATIONS.

Gram-positive bacteria

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus ppneumoniae

Streptococcus pyogenes

Gram-negative bacteria

Haemophilus ducreyi

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

“Other” bacteria

Chlamydophila pneumoniae

Chlamydia trachomatis

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration MIC) less than or equal to the azithromycin susceptible breakpoint of ≤ 4mcg/mL. However, safety and effectiveness of azithromycin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials.

Gram-positive bacteria

Beta-hemolytic streptococci (Groups C, F, G)

Viridans group streptococci

Gram-negative bacteria

Bordetella pertussis

Anaerobic bacteria

Peptostreptococcus

species Prevotella bivia

“Other” bacteria

Ureaplasma urealyticum

Legionella pneumophila

Mycoplasma hominis

Activity of Azithromycin against Mycobacterium avium complex (MAC):

In vitro azithromycin has demonstrated activity against Mycobacterium avium complex (MAC) bacteria. Azithromycin has also been shown to be active against phagocytized MAC bacteria in mouse and human macrophage cell cultures.

Susceptibility Testing Methods:

When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use but could aid the physician in selecting the most effective antimicrobial.

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentration and standardized concentration of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentration. This procedure uses paper disks impregnated with 15-mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion interpretive criteria are provided in Table 1.

Table 1. Susceptibility Interpretive Criteria for

Azithromycin Susceptibility Test Result Interpretive

Criteria

Susceptibility to azithromycin must be tested in ambient air.

aInsufficient information is available to determine Intermediate or Resistant interpretive criteria

The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues.

A report of “susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of “intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. Standard azithromycin powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the azithromycin 15 mcg disk, the criteria in Table 2 should be achieved.

Table 2. Acceptable Quality Control Ranges for Azithromycin

Susceptibility to azithromycin must be tested in ambient air.

*ATCC = American Type Culture Collection

16 NON-CLINICAL TOXICOLOGY

General 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.

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.

Subacute and Chronic Toxicity:

Reproductive Toxicology:

Developmental Toxicology:

Neonatal Studies:

Carcinogenicity:

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

Genotoxicity:

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 μg/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 μg/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 μg/mL in the presence and 7.5 μg/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.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ZITHROMAX^® (Azithromycin dihydrate; tablets: 250 mg and 600 mg, powder for oral suspension: 100 mg/5mL and 200mg/5mL when reconstituted, and injection: 500 mg/vial or 500 mg/5mL when reconstituted), Submission Control 270217, Product Monograph, Pfizer Canada ULC. (April 27, 2023)