Azithromycin for Injection (Jamp Pharma) 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. 1 INDICATIONS ............................................................................................................... 4

   1. 1.1 Pediatrics ............................................................................................................... 6
   2. 1.2 Geriatrics ............................................................................................................... 7
2. 2 CONTRAINDICATIONS ................................................................................................. 7

3. 4 DOSAGE AND ADMINISTRATION ................................................................................. 7

   1. 4.1 Dosing Considerations ........................................................................................... 7
   2. 4.2 Recommended Dose and Dosage Adjustment ....................................................... 7
   3. 4.3 Reconstitution ..................................................................................................... 11

4.5 Missed Dose ......................................................................................................... 13

1. 5 OVERDOSAGE ............................................................................................................ 13
2. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................... 13

3. 7 WARNINGS AND PRECAUTIONS ................................................................................ 15

   1. 7.1 Special Populations .............................................................................................. 18
   2. 7.1.1 Pregnant Women ........................................................................................... 18
   3. 7.1.2 Breast-feeding ................................................................................................ 19
   4. 7.1.3 Pediatrics ....................................................................................................... 19
   5. 7.1.4 Geriatrics ........................................................................................................ 20

4. 8 ADVERSE REACTIONS ................................................................................................ 20

   1. 8.1 Adverse Reaction Overview ................................................................................. 20
   2. 8.2 Clinical Trial Adverse Reactions ............................................................................ 20
   3. 8.2.1 Clinical Trial Adverse Reactions – Pediatrics .......................................................... 23
   4. 8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................ 25
   5. 8.5 Post-Market Adverse Reactions ........................................................................... 27

5. 9 DRUG INTERACTIONS ................................................................................................ 28

   9.2 Drug Interactions Overview ................................................................................. 28

   1. 9.4 Drug-Drug Interactions ........................................................................................ 28
   2. 9.5 Drug-Food Interactions ........................................................................................ 33
   3. 9.6 Drug-Herb Interactions ........................................................................................ 33
   4. 9.7 Drug-Laboratory Test Interactions ....................................................................... 33

6. 10 CLINICAL PHARMACOLOGY ....................................................................................... 33

   1. 10.1 Mechanism of Action ..................................................................................... 33
   2. 10.2 Pharmacodynamics ........................................................................................ 34
   3. 10.3 Pharmacokinetics ........................................................................................... 34
7. 11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 37
8. 12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 38

PART II: SCIENTIFIC INFORMATION ....................................................................................... 39

1. 13 PHARMACEUTICAL INFORMATION ............................................................................ 39
2. 14 CLINICAL TRIALS ........................................................................................................ 39
3. 15 MICROBIOLOGY ........................................................................................................ 45
4. 16 NON-CLINICAL TOXICOLOGY ..................................................................................... 48
5. 17 SUPPORTING PRODUCT MONOGRAPHS…………………………………………………………………….65

PATIENT MEDICATION INFORMATION .................................................................................. 66

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

Azithromycin for Injection

Azithromycin for Injection (azithromycin dihydrate) is indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below.

Azithromycin for Injection should be followed by oral administration of azithromycin as required (see 4 DOSAGE AND ADMINISTRATION).

Adults

Lower Respiratory Tract:

Community-acquired pneumonia (CAP) due to Chlamydia pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients who require initial intravenous therapy.

Genitourinary Tract:

Pelvic inflammatory disease (PID) due to Chlamydia trachomatis, Neisseria gonorrhoeae or Mycoplasma hominis in patients who require initial intravenous therapy. If anaerobic organisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin for Injection.

Patients should have a serologic test for syphilis performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for this disease should be initiated if infection is confirmed.

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

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Azithromycin for Injection and other antibacterial drugs, Azithromycin for Injection 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

Azithromycin for Injection

Pediatrics (< 16 years): The safety and effectiveness of Azithromycin for Injection have not been established. See 7.1.3 Pediatrics

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

Azithromycin for Injection (azithromycin dihydrate) 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:

Due to the lack of data, Azithromycin for Injection should be used with caution in patients with hepatic impairment.

Renal Impairment:

Due to the lack of data, Azithromycin for Injection should be used with caution in patients with renal impairment (including patients on dialysis).

1. 4.2 Recommended Dose and Dosage Adjustment

ADULTS

Azithromycin for Injection must be reconstituted and diluted as directed, and administered as an intravenous infusion over at least 60 minutes. Do not administer as an intravenous bolus or an intramuscular injection (see 7 WARNINGS AND PRECAUTIONS in the Product Monograph).

Intravenous therapy should be followed by oral azithromycin dihydrate. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

The infusate concentration and rate of infusion for Azithromycin for Injection should be either 1 mg /mL over 3 hours, or 2 mg / mL over 1 hour.

COMMUNITY-ACQUIRED PNEUMONIA: in patients who require initial intravenous therapy:

The recommended dose is 500 mg I.V. as a single daily infusion for at least 2 days followed by oral therapy at 500 mg daily to complete a 7-10-day course of therapy.

PELVIC INFLAMMATORY DISEASE:

The recommended dose is 500 mg I.V. as a single daily infusion for at least 1 day followed by oral therapy at 250 mg daily to complete a 7-day course of therapy. Note: If anaerobic organisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin for Injection.

4.3 Reconstitution

Azithromycin for Injection:

Prepare the initial solution of Azithromycin for Injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial. Shake the vial until all of the drug is dissolved. Since the vial is evacuated, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact volume of 4.8 mL is dispensed. Each mL of reconstituted solution contains azithromycin dihydrate equivalent to 100 mg azithromycin. Reconstituted solution is stable for 24 hours when stored below 30°C. The reconstituted solution must be further diluted prior to administration.

Dilution of reconstituted solution: To provide azithromycin over a concentration range of 1.0 -

2.0 mg / mL, transfer 5 mL of the 100 mg / mL azithromycin solution into the appropriate amount of the following diluents:

Diluted solutions prepared in this manner are stable for 24 hours at or below room temperature (30°C), or for 72 hours if stored under refrigeration (5°C). As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should be discarded.

Only limited data are available on the compatibility of Azithromycin for Injection with other intravenous substances, therefore additives or other medications should not be added to Azithromycin for Injection or infused simultaneously through the same intravenous line. If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of Azithromycin for Injection with an infusion solution compatible with Azithromycin for Injection and with any other drug(s) administered via the common line. If Azithromycin for Injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug.

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.

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

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

Up to 15 grams cumulative dose of Azithromycin for Injection (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

Azithromycin for Injection 500 mg: Each vial contains azithromycin dihydrate in a lyophilized form equivalent to 500 mg azithromycin for injection. After reconstitution, each mL contains azithromycin dihydrate equivalent to 100 mg azithromycin (500 mg / 5 mL) (see 4 DOSAGE AND ADMINISTRATION, 4.3 Reconstitution). Azithromycin for Injection is supplied in cartons of 10 single use vials.

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.

  Intravenous Administration

• Azithromycin for injection should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes. Do not administer as an intravenous bolus or an intramuscular injection (see 4 DOSAGE AND ADMINISTRATION).

• Local injection site reactions have been reported with the intravenous administration of azithromycin dihydrate. The incidence and severity of these reactions were the same when 500 mg azithromycin was given over 1 hour (2 mg/mL as 250 mL infusion) (see 8 ADVERSE REACTIONS). All volunteers who received infusate concentrations above 2.0 mg/mL experienced local I.V. site reactions, therefore, higher concentrations should be avoided.

  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 repolarisation 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 Azithromycin for Injection in these patients is not recommended.

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 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).

Due to the lack of data, Azithromycin for Injection should be used with caution in patients with hepatic impairment.

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 for Injection. 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 Azithromycin for Injection 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 for Injection 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 10-80 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).

Due to the lack of data, Azithromycin for Injection should be used with caution in patients with renal impairment (including patients on dialysis).

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 for Injection 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

  Azithromycin for Injection 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 Azithromycin for Injection therapy, if the lactating mother is treated with Azithromycin for Injection, 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 (< 16 years of age): The safety and effectiveness of Azithromycin for Injection have not been established.

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

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.

* 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

1. 8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Oral Regimen: Children

Single and Multiple-dose regimens:

In children enrolled in controlled clinical trials in acute otitis media and S. pyogenes pharyngitis, the types of side effects were comparable to those seen in adults (see below).

Different side effect incidence rates for the dosage regimens recommended in children were observed.

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

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

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

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

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).

Children:

One-, Three- and Five-Day Regimens

Laboratory data collected from 64 subjects receiving azithromycin in comparative clinical trials employing the 1-day regimen (30 mg/kg as a single dose), 1198 and 169 subjects receiving azithromycin respectively employing the two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.

Similar results were obtained in subjects receiving the two 5-day regimens. Overall, 1948 and 421 patients were exposed to 30 mg/kg or 60 mg/kg, respectively in divided doses over 5 days. The data collected in the subset of azithromycin patients assessed for laboratory abnormalities were similar to those in all comparators combined with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.

In a single center clinical trial, a decrease in absolute neutrophils was observed in the range of 21-29% for azithromycin regimens of 30 mg/kg given either as a single dose or over 3 days, as well as the comparator. No patients had significant neutropenia defined as an absolute neutrophil count <500 cells/mm³ (see 14 CLINICAL TRIALS).

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

Intravenous Therapy

Adults:

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

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

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

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

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

I.V. dosing.

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 azithromycin dihydrate 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 and powder for oral suspension 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.

1. 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 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

Intravenous Administration:

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

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

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

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

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

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

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

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 (C_max) was increased by 56% while the extent of absorption (AUC) was unchanged. Food does not affect the absorption of azithromycin in the tablet dosage form. Azithromycin tablets and powder for oral suspension can be taken with or without food.

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 Pediatrics:

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

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

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

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

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

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

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

^a Arithmetic means

^B maximum weight for 3-day regimen was < 25 kg and for 5-day regimen was <41.7 kg

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

Azithromycin for Injection:

Dry powder: Store at controlled room temperature,15-30°C.

Diluted solution: Stable for 24 hours at or below 30°C, or for 72 hours if stored under refrigeration (5°C). For single-use only. Discard any unused portion after use.

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: C₃₈H₇₆N₂0₁₄ and 785.02 g/mol

Structural formula:

Physicochemical properties: Azithromycin dihydrate is a white to off-white crystalline powder of uniform appearance. The aqueous solubility at pH 7.4 at 37°C is 39 mg/mL. The powder is nonhygroscopic.

pK_a: 8.48

Melting point: 125°C

14 CLINICAL TRIALS

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.

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 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 ≤ 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.

^a Insufficient 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 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. ^pr ZITHROMAX® powder for solution, 500 mg/vial azithromycin (as azithromycin dihydrate), 100 mg/mL when reconstituted for injection, submission control 270217, Product Monograph, Pfizer Canada ULC. (APR 27, 2023)