Azithromycin for Injection, USP (Hospira Healthcare) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Azithromycin for Injection, USP 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, USP should be followed by oral administration of azithromycin as required (see 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, USP.

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, USP 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, USP and other antibacterial drugs, Azithromycin for Injection, USP 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.

CONTRAINDICATIONS

Azithromycin for Injection, USP is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin and in those with 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 DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

General

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 therapy (see CONTRAINDICATIONS). Allergic reactions may occur during and soon after treatment with Azithromycin for Injection, USP. 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.

The use of azithromycin with other drugs may lead to drug-drug interactions. For established or potential drug interactions, see DRUG INTERACTIONS section of the product monograph.

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, USP in these patients is not recommended.

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.

As with any antibacterial preparation, observation for signs of superinfection with nonsusceptible organisms, including fungi is recommended.

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

Intravenous Administration:

Azithromycin for Injection, USP 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 DOSAGE AND ADMINISTRATION).

Local injection site reactions have been reported with the intravenous administration of Azithromycin for Injection, USP. 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 ADVERSE REACTIONS). All volunteers who received infusate concentrations above 2.0 mg/mL experienced local intravenous 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 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 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 ADVERSE REACTIONS, Post Market Adverse Drug 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 ACTION AND CLINICAL PHARMACOLOGY, Cardiac Electrophysiology).

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 Clostridium difficile. Clostridium 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 Clostridium 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 Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see 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

Due to the lack of data, Azithromycin for Injection, USP 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. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur (see ADVERSE REACTIONS).

Musculoskeletal and connective tissue disorders

Myasthenia gravis:

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 for Injection, USP 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, USP is administered to patients with GFR < 10 mL/min. This precaution is based on a clinical study of azithromycin immediate-release tablets, in which patients with GFR < 10 mL/min showed a significant (61%) increase in mean Cmax and a significant (35%) increase in systemic exposure to azithromycin, and experienced a high incidence of gastrointestinal adverse events (8 of 19 clinical study subjects). Patients with GFR 10-80 mL/min showed only slightly increased serum azithromycin levels compared to patients with normal renal function.

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

Sexual Function/Reproduction

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 TOXICOLOGY).

Susceptibility/Resistance

Development of drug resistant bacteria

Prescribing Azithromycin for Injection, USP 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.

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. Azithromycin for Injection, USP should not be used during pregnancy unless the expected benefit to the mother outweighs any potential risk to the fetus. 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 TOXICOLOGY).

Nursing Women:

Azithromycin has been reported to have been secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk. In addition, the safety of azithromycin has not been studied in infants less than 6 months of age. Therefore, Azithromycin for Injection, USP should not be used in the treatment of nursing women unless the expected benefit to the mother outweighs any potential risk to the infant. Because azithromycin may accumulate in breast milk over time with continued Azithromycin for Injection, USP therapy, if the lactating mother is treated with Azithromycin for Injection, USP, the breast milk should be expressed and discarded during treatment.

Pediatrics:

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

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

Pharyngitis and tonsillitis: Safety and efficacy in the treatment of children with pharyngitis and tonsillitis under 2 years of age have not been established.

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

Infantile hypertrophic pyloric stenosis (IHPS)

Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs.

The safety and effectiveness of Azithromycin in children or adolescents under 16 years have not been established.

Prevention of Disseminated Mycobacterium Avium Complex (MAC) Disease:

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

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

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).

Monitoring and Laboratory Tests

Monitoring of QT/QTc intervals during treatment with Azithromycin for Injection, USP may be considered by the physician as appropriate.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with oral azithromycin 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 therapy because of drug related side effects. Among adults receiving azithromycin intravenously, 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%).

In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was

0.4%. In clinical trials in children given 30 mg/kg, orally either as a single dose (n=487) or over 3 days, (n=1729) discontinuation from therapy due to treatment-related side effects was approximately 1%.

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

Clinical Trial Adverse Drug Reactions

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

Intravenous/Oral Regimen: Adults

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

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

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

Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis

Nervous System: headache, somnolence

Allergic: bronchospasm

Special Senses: taste perversion

Abnormal Hematologic and Clinical Chemistry Findings

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 intravenous/oral azithromycin less than 2% of patients discontinued therapy because of treatment-related liver enzyme abnormalities.

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

Post-Market Adverse Drug Reactions

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

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

WARNINGS AND PRECAUTIONS), serum sickness, urticaria, vasculitis, angioedema, pruritus;

Blood and the

lymphatic system Agranulocytosis, hemolytic anemia, thrombocytopenia. disorders

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

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

General: Asthenia, paresthesia, fatigue, muscle pain;

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

Liver/Biliary: Hepatic 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 WARNINGS AND PRECAUTIONS).

Musculoskeletal

and connective

tissue disorders:

myasthenia gravis

Nervous System: Dizziness, hyperactivity, hypoaesthesia, seizure, convulsions, and syncope

Psychiatric

Disorders:

Aggressive reaction, anxiety, nervousness, agitation, delirium, hallucinations

Skin/Appendages: Serious skin reactions including erythema multiforme, exfoliative dermatitis,

Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) (see 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.

DRUG INTERACTIONS

Overview

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 WARNINGS AND PRECAUTIONS, Cardiovascular and ADVERSE REACTIONS, Post-Marketing Experience).

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.

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.

Drug-Drug Interactions

Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical; UNK=Unknown

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 / P-glycoprotein substrates

Concomitant administration of some macrolide antibiotics with P-glycoprotein substrates, including digoxin, 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.

Drug-Food Interactions

Azithromycin tablets and powder for oral suspension can be taken with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

General

Hepatic Impairment:

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

Renal Impairment:

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

Recommended Dose and Dosage Adjustment

ADULTS

Azithromycin for Injection, USP 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 WARNINGS AND PRECAUTIONS). Intravenous therapy should be followed by oral azithromycin. 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, USP 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 intravenous 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 intravenous 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, USP.

Administration

Reconstitution:

FLIPTOP VIAL

Prepare the initial solution of Azithromycin for Injection, USP 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 monohydrate equivalent to 100 mg azithromycin. Reconstituted solution is stable for 24 hours when stored between 20 and 25°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 room temperature (20 to 25°C), or for 7 days if stored under refrigeration (5°C). As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should be discarded.

Only limited data are available on the compatibility of Azithromycin for Injection, USP with other intravenous substances, therefore additives or other medications should not be added to Azithromycin for Injection, USP 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, USP with an infusion solution compatible with Azithromycin for Injection, USP and with any other drug(s) administered via the common line. If Azithromycin for Injection, USP 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.

ADD-Vantage^TM Vial

Dilution of reconstituted solution:

Azithromycin for Injection, USP, when reconstituted with the solutions listed below to 2 mg/mL concentration, is stable for 24 hours between 20 and 25°C and 7 days at 5°C conditions.

Admixture containers available

The ADD-Vantage vial should be joined with a 250 mL ADD-Vantage flexible diluent container (5% dextrose injection or 0.9% sodium chloride injection or 0.45% sodium chloride injection). The diluted solution contains 2 mg/mL of azithromycin, on dilution with 250 mL of diluent.

INSTRUCTIONS FOR USE OF THE ADD-Vantage^TM VIAL

To Open Diluent Container

Peel overwrap from the corner and remove container. Some opacity of the plastic is due to moisture absorption during the sterilization process and may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container: (Use Aseptic Technique)

1. 1.

   Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:

   a. To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (see Figure 1), pull the ring approximately half way around the cap and then pull straight up to remove the cap (see Figure 2).

   NOTE: Do not access vial with syringe.

   b. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (See Figure 3.)

2. 2.

   Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED

   IN TIGHTLY TO ASSURE A SEAL. This occurs approximately 1/2 turn (180°) after the first audible click. (See Figure 4.) The clicking sound does not assure a seal, the vial must be turned as far as it will go.

   NOTE: Once vial is sealed, do not attempt to remove. (See Figure 4.)

3. 3. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
4. 4. Label appropriately.

To Prepare Admixture

1. 1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
2. 2. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (See Figure 5.)
3. 3. Pull the inner cap from the drug vial. (See Figure 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
4. 4. Mix container contents thoroughly and use within the specified time.
5. 5. Look through the bottom of the vial to verify that the stopper has been removed and complete mixing has occurred (See Figure 7.) If the rubber stopper is not removed from the vial and medication is not released on the first attempt, the inner cap may be manipulated back into the rubber stopper without removing the drug vial from the diluent container. Repeat step 3 through 5.

Preparation for Administration:

1. 1. Confirm the activation and admixture of vial contents.
2. 2. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
3. 3. Close flow control clamp of administration set.
4. 4. Remove cover from outlet port at bottom of container.
5. 5. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
6. 6. Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
7. 7. Squeeze and release drip chamber to establish proper fluid level in chamber.
8. 8. Open flow control clamp and clear air from set. Close clamp.
9. 9. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
10. 10. Regulate rate of administration with flow control clamp.

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 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Azithromycin for Injection, USP (azithromycin monohydrate), 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.

Pharmacodynamics

Cardiac Electrophysiology:

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial. A total of 119 healthy subjects were enrolled (mean age of 35.5 years; range 18-55 years), of which 116 subjects (97 males) completed the study and were included in the analysis. Subjects were randomized to one of 5 treatments and received orally once daily for 3 days: placebo, chloroquine 600 mg base only, or chloroquine 600 mg base in combination with azithromycin 500 mg, 1000 mg, and 1500 mg. On Day 3, the azithromycin mean (%CV) plasma Cmax values for the 500, 1000 and 1500 mg azithromycin dose regimens were 0.536 (33), 0.957 (31), and 1.54 (28) 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.

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.

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.

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

^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.

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), (see DETAILED PHARMACOLOGY).

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, (see DETAILED PHARMACOLOGY).

Excretion:

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, (see DETAILED PHARMACOLOGY).

Special Populations and Conditions

Pediatric Pharmacokinetics:

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

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

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

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

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

Gender:

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 mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). The mean C_max and AUC_0-120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min).

STORAGE AND STABILITY

Dry Powder: Store at controlled room temperature conditions (20 to 25°C)

Flip Top Vial:

Reconstituted Solution: Stable for 24 hours stored at controlled room temperature (20 to 25°C).

Diluted solution: Stable for 24 hours between 20 to 25°C, or for 7 days if stored under refrigeration (5°C). For single-use only. Discard any unused portion after use.

ADD-Vantage Vial:

Reconstituted Solution: Stable for 24 hours at controlled room temperature (20 to 25°C), or 7 days if stored under refrigeration (5°C).

DOSAGE FORMS, COMPOSITION AND PACKAGING

Azithromycin for Injection, USP 500 mg: Each vial contains azithromycin monohydrate in a lyophilized form equivalent to 500 mg azithromycin. The non-medicinal ingredients include: 392 mg (ADD Vantage) and 384.6 mg (Flip Top) of anhydrous citric acid and sodium hydroxide for pH adjustment. After reconstitution, each mL contains azithromycin monohydrate equivalent to 100 mg azithromycin (see DOSAGE AND ADMINISTRATION, Reconstitution Directions).

Flip Top Vial:

Cartons of 10 single dose vials.

Provides 500 mg/5 mL (100 mg/mL) azithromycin when reconstituted as directed.

ADD-Vantage Vial

Carton of 10 Single Use ADD-Vantage^TM vials of 500 mg. Provides 500 mg/250 mL (2 mg/mL) azithromycin when reconstituted as directed in a 250 mL ADD-Vantage flexible diluant container.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: azithromycin monohydrate Chemical Name: 9-deoxo-9α-aza-9α-methyl-9α-homoerythromycin A monohydrate. Molecular Formula: C₃₈H₇₂N₂0₁₂·H₂O Molecular Weight: 767.02 g/mol

Structural Formula:

Phisiochemical

properties:

Azithromycin monohydrate is a white to off-white crystalline powder of uniform appearance. pH is between 9.0 and 11.0. The powder is non-hygroscopic.

pK_a: 8.74

Melting point: 133°C-135°C

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 21-24. 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 INDICATIONS AND CLINICAL USE): Two randomized, double-blind clinical trials were performed in patients with CD4 counts < 100 cells/mcL. The first study compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcL. 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/mcL. 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%).

DETAILED PHARMACOLOGY

Following oral administration, azithromycin is rapidly absorbed (T_max = 2-3 hours) and distributed widely throughout the body. Rapid movement of azithromycin from blood into tissue results in significantly higher azithromycin concentrations in tissue than in plasma (up to 50 times the maximum observed concentration in plasma). The absolute bioavailability is approximately 37%.

Adults:

Following administration of a 500 mg oral dose, the maximum serum concentration (C_max) is 0.4 mcg/mL and is attained 2-3 hours after dosing with areas under the curve of 2.6 mcg•hr/mL ( AUC 0-24) and 3.7 mcg•hr/mL ( AUC 0-48₎ and trough levels of 0.05 mcg/mL. These oral values are approximately 38%, 83% and 52% of the values observed following a single 500 mg intravenous 3 -hour infusion: C_max 1.08 mcg/mL, trough level 0.06 mcg/mL, and AUC24 5.0 mcg•hr/mL. Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval. Also refer to tabulated pharmacokinetic data reported in adults under ACTION AND CLINICAL PHARMACOLOGY, Adult Pharmacokinetics section. When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

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

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

2 x 250 mg on Day 1 followed by one 250 mg on Days 2 through 5

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

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

Mean AUC_0∞ for both regimens were similar, with a ratio of AUC_0∞(3-day)/AUC_0∞(5-day) of 105% (90% CI=93, 120). Serum concentrations of azithromycin declined in a polyphasic pattern resulting in average terminal half-life of 68.6 hours for the 3-day regimen and about 66 hours for the 5-day regimen.

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

The table below compares pharmacokinetic parameters following single oral doses of 500 mg azithromycin with those obtained after a single 500 mg intravenous 3-hour infusion.

Pharmacokinetic parameters in adults after oral

and intravenous administration of 500 mg azithromycin

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

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

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

* Samples were obtained 2-24 hours after the first dose ** Dosing regimen of 2 doses of 250 mg each, separated by 12 hours *** Sample was obtained 19 hours after a single 500 mg dose

The extensive tissue distribution is confirmed by examination of other tissues (prostate; ovary, uterus and salpinx; stomach; liver and gallbladder), in which azithromycin is present in concentrations of 2 mcg/g tissue or greater. However, only very low concentrations are noted in cerebrospinal fluid (less

than 0.01 mcg/mL) of noninflamed meninges. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy.

When azithromycin oral suspension as the 200 mg/5mL dose 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.

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

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

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

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

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

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

The absolute bioavailability of two 600 mg Azithromycin tablets was 34%. Administration of two 600 mg tablets with food increased C_max by 31% while the extent of absorption (AUC) was unchanged.

Children:

When azithromycin was dosed at 10 mg/kg day 1, followed by 5 mg/kg days 2 through 5 in children 1 to 15 years old, the mean pharmacokinetic parameters on day 5 were:

Pharmacokinetic parameters in pediatric subjects on day 5

at dosage 10 mg/kg (day 1) and 5 mg/kg (days 2-5)*

* Dose administered as Powder for Oral Suspension

Two clinical studies were conducted in 68 children 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 over either 3 or 5 days.

Both studies were open, non-comparative trials. Drug was administered following a low-fat breakfast in order to assess the effect of food on absorption and safety.

The first study consisted of 35 pediatric subjects treated with 20 mg/kg/day (maximum daily dose of 500 mg) for 3 days of whom 34 subjects were evaluated for pharmacokinetics.

In the second study, 33 pediatric subjects received doses of 12 mg/kg/day (maximum daily dose of 500 mg) for 5 days of whom 31 subjects were evaluated for pharmacokinetics.

In both studies, azithromycin levels were determined over a 24-hour period following the last daily dose. Subjects weighing above 25.0 kg in the 3-day study or 41.7 kg in the 5-day study received the maximum adult daily dose of 500 mg. Eleven subjects (weighing 25.0 kg or less) in the first study and 17 subjects (weighing 41.7 kg or less) in the second study received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of children who received a total dose of 60 mg/kg.

Single dose pharmacokinetics in children given doses of 30 mg/kg has not been studied.

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 the INDICATIONS-section.

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^54,52 (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^{52, 53} 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

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 Studies

Fetotoxicity Teratology

Neonatal Studies

Carcinogenicity

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

Genetic Toxicology

Azithromycin was examined in several genetic toxicology assays for induction of gene mutations in microbial and mammalian cells and for chromosomal mutations in vivo and in vitro. No evidence of genotoxic activity was observed in any of the following assays:

Microbial Assay: Tests were conducted on strains TA 1535, TA 1537, TA 98 and TA 100 of Salmonella typhimurium at concentrations up to 2 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 to 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.

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