Apo-Azithromycin Z Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

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

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

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

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

1.1 Pediatrics ...................................................................................................................... 5

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

2 CONTRAINDICATIONS ..................................................................................................... 6

4 DOSAGE AND ADMINISTRATION .................................................................................... 6

4.1 Dosing Considerations .................................................................................................. 6

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

4.5 Missed Dose .................................................................................................................. 7

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

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .................................... 8

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

7.1 Special Populations ..................................................................................................... 12

7.1.1 Pregnant Women ..................................................................................................... 12

7.1.2 Breast-feeding .......................................................................................................... 12

7.1.3 Pediatrics .................................................................................................................. 13

7.1.4 Geriatrics .................................................................................................................. 13

8 ADVERSE REACTIONS .................................................................................................... 13

8.1 Adverse Reaction Overview ........................................................................................ 13

8.2 Clinical Trial Adverse Reactions .................................................................................. 14

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 ............................................................................................... 17

9.5 Drug-Food Interactions ............................................................................................... 24

9.6 Drug-Herb Interactions ............................................................................................... 24

9.7 Drug-Laboratory Test Interactions .............................................................................. 24

10 CLINICAL PHARMACOLOGY ........................................................................................... 24

10.1 Mechanism of Action ................................................................................................ 24

10.2 Pharmacodynamics .................................................................................................. 25

10.3 Pharmacokinetics ..................................................................................................... 25

11 STORAGE, STABILITY AND DISPOSAL............................................................................. 27

12 SPECIAL HANDLING INSTRUCTIONS .............................................................................. 27

PART II: SCIENTIFIC INFORMATION ........................................................................................ 28

13 PHARMACEUTICAL INFORMATION ............................................................................... 28

14 CLINICAL TRIALS ........................................................................................................... 28

14.2 Comparative Bioavailability Studies.......................................................................... 28

15 MICROBIOLOGY ............................................................................................................ 30

16 NON-CLINICAL TOXICOLOGY ......................................................................................... 33

17 SUPPORTING PRODUCT MONOGRAPHS ....................................................................... 63

PATIENT MEDICATION INFORMATION ................................................................................... 64

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

APO-AZITHROMYCIN Z for Oral Administration

APO-AZITHROMYCIN Z (azithromycin 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 APO-AZITHROMYCIN Z may be initiated before results of these tests are known; once the results become available, antibiotic treatment should be adjusted accordingly.

Adults

Pharyngitis and tonsillitis:

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

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

Acute bacterial exacerbations of chronic obstructive pulmonary disease:

Acute bacterial exacerbations of chronic obstructive pulmonary diseases caused by 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of APO-AZITHROMYCIN Z and other antibacterial drugs, APO-AZITHROMYCIN Z should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

1.1 Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of APO-AZITHROMYCIN Z in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

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

APO-AZITHROMYCIN Z (azithromycin tablets) 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

Hepatic Impairment:

No dose adjustment of APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z is recommended for subjects with GFR 10 to 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

APO-AZITHROMYCIN Z for ORAL THERAPY

ADULTS

DOSING in relation to FOOD:

APO-AZITHROMYCIN Z tablets can be taken with or without food.

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

The recommended dose of APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z 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.

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.

For management of a suspected drug overdose, contact your regional poison control centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Dosage Form and Packaging:

APO-AZITHROMYCIN Z Tablets, 250 mg: Each white coloured, film-coated, oval shaped biconvex tablet, engraved “APO” on one side and “AZ250” on the other side, contains azithromycin dihydrate equivalent to 250 mg of azithromycin. Available in HDPE bottles of 100 tablets and unit dose blister of 6 tablets.

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.

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 hypokalaemia 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 APO-AZITHROMYCIN Z 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.

Clostridium difficile associated disease

Clostridium 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 APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z. 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 APO-AZITHROMYCIN Z 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 in patients with renal impairment have not been established. No dose adjustment is recommended for patients with GFR 10 to 80 mL/min. Caution should be exercised when APO-AZITHROMYCIN 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 C_max 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 to 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 APO-AZITHROMYCIN Z 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 mcg/mL (see 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

APO-AZITHROMYCIN Z 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 APO-AZITHROMYCIN Z therapy, if the lactating mother is treated with APO-AZITHROMYCIN Z, 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.

7.1.3 Pediatrics

Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of APO-AZITHROMYCIN Z in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

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. 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 adult patients (n=3812) from the 5-day multiple dose clinical trials discontinued azithromycin therapy because of drug related side effects.

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 therapy were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, along with abdominal pain and rashes. 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 were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3 to 4%), abdominal pain (2 to 3%), 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 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.

Oral Regimen: Adults

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

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.

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.

Allergic: Arthralgia, edema, anaphylaxis (with rare reports of fatalities) (see 7 WARNINGS AND PRECAUTIONS), serum sickness, urticaria, vasculitis, angioedema;

Blood and the

lymphatic system Agranulocytosis, haemolytic anaemia, thrombocytopenia

disorders:

Cardiovascular: Cardiac arrhythmias (including ventricular tachycardia), palpitations, hypotension. There have been rare reports of QT prolongation and torsade 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 7 WARNINGS AND PRECAUTIONS).

Gastrointestinal: Anorexia, constipation, hypoglycaemia, dehydration, vomiting/diarrhea rarely resulting in dehydration, pancreatitis, pseudomembranous colitis, rare reports of tongue discoloration, pyloric stenosis / infantile hypertrophic pyloric stenosis (IHPS);

General: Asthenia, paresthesia, muscle pain;

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

Liver/Biliary: Hepatitis fulminant. 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 resulted in death (see 7 WARNINGS AND PRECAUTIONS).

Musculoskeletal

and connective Myasthenia gravis

tissue disorders:

Nervous System: Hyperactivity, hypoaesthesia, seizure, convulsions, and syncope

Psychiatric Aggressive reaction, anxiety, nervousness, agitation, delirium,

Disorders: hallucinations

Skin/Appendages: Serious skin reactions including erythema multiforme, exfoliative dermatitis, Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) (see 7 WARNINGS AND PRECAUTIONS).

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

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 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

APO-AZITHROMYCIN Z 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 to 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 C_max values for the 500, 1000 and 1500 mg azithromycin dose regimens were 0.536 (33), 0.957 (31), and 1.54 (28) mcg/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 to 3 hours) and distributed widely throughout the body.

The absolute bioavailability is approximately 37%.

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 mcg/mL to 7% at 2.0 mcg/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 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 APO-AZITHROMYCIN Z Film-Coated Tablets at controlled room temperature (15°C to 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

14 CLINICAL TRIALS

14.2 Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of APO-AZITHROMYCIN Z 250 mg tablets (Apotex Inc.) with ZITHROMAX® 250 mg tablets (Pfizer Canada Inc.) was conducted in healthy, adult, Asian male subjects under fasting conditions. Comparative bioavailability data from the 66 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ APO-AZITHROMYCIN Z (azithromycin dihydrate) tablets, 250 mg (Apotex Inc.)

² ZITHROMAX^® (azithromycin dihydrate) tablets, 250 mg (Pfizer Canada Inc.)

³ Expressed as the median (range) only

Due to the long elimination half-life of azithromycin, AUC_I and T_1/2 could not be accurately calculated from the data obtained in this study.

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

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 to 24. For the 377 patients analyzed in the MITT analysis at the Day 21 to 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:

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 pneumoniae

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 ≤ 4 mcg/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

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:

Development 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 mcg/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 mcg/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 mcg/mL in the presence and 7.5 mcg/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 tablets 250 mg and 600 mg, oral suspension 100 mg/5 mL and 200 mg/5 mL, Injection 500 mg/vial), submission control 270217, Product Monograph, Pfizer Canada ULC. (APR 27, 2023)