HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Zmax
`safely and effectively. See full prescribing information for Zmax.
`
`Zmax® (azithromycin extended release) for oral suspension
`Initial U.S. Approval: 1991
`
`To reduce the development of drug-resistant bacteria and maintain the
`effectiveness of Zmax and other antibacterial drugs, Zmax should be used
`only to treat infections that are proven or strongly suspected to be caused by
`susceptible bacteria.
`
`-----------------------RECENT MAJOR CHANGES------------------------------
`
`WARNINGS AND PRECAUTIONS, QT prolongation (5.5)
`
`1/2013
`
`-------------------------INDICATIONS AND USAGE-----------------------------
`Zmax is a macrolide antimicrobial indicated for mild to moderate infections
`
`caused by designated, susceptible bacteria:
`
` Acute bacterial sinusitis in adults (1)
`
` Community-acquired pneumonia in adults and children 6 months and older
`
`(1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
` Adults: 2 g as a single dose; consume contents of full bottle (2.1)
` Pediatric: 60 mg/kg (1 mL of suspension per pound body weight;
`equivalent to 27 mg/lb) as a single dose, up to a maximum of 2 g (2.2)
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Bottle containing 2 g azithromycin for constitution with 60 mL of water (final
`concentration 27 mg/mL) (3)
`
`----------------------WARNINGS AND PRECAUTIONS------------------------
` Severe (including fatal) allergic and skin reactions: Discontinue Zmax if
`reaction occurs. (5.1)
` Hepatotoxicity: severe, and sometimes fatal, hepatotoxicity has been
`reported. Discontinue immediately if signs and symptoms of hepatitis
`occur. (5.2)
` Clostridium difficile-associated diarrhea: Evaluate patients if diarrhea
`occurs. (5.3)
` Exacerbation of myasthenia gravis (5.4)
` Prolongation of the QT interval and cases of torsades de pointes have been
`reported. Avoid use in patients with known prolongation, those with
`
`hypokalemia, and with other drugs that prolong the QT interval. (5.5)
`
` Gastrointestinal Disturbances: higher incidence in patients with GFR<10
`
`mL/min. (5.6)
`
`------------------------ADVERSE REACTIONS------------------------------------
`Most common adverse reactions (incidence >1%) are diarrhea/loose stools,
`nausea, abdominal pain, headache, and vomiting (6.1, 6.2)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc at
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
`
`---------------------------DRUG INTERACTIONS---------------------------------
`Warfarin: Use with azithromycin may increase coagulation times; monitor
`prothrombin time (7)
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`Pediatric use:
` Safety and efficacy in the treatment of patients under 6 months of age have
`not been established. (8.4)
`
`---------------------------CONTRAINDICATIONS--------------------------------
`Hypersensitivity to azithromycin, erythromycin, or any macrolide or ketolide
`
`antibiotic (4.1)
`
`History of cholestatic jaundice/hepatic dysfunction associated with prior use
`
`of azithromycin (4.2)
`
`__________________________________________________________________________________________________
`
`Revision Date: 8/2013
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling
`
`3
`4
`
`12.3 Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, mutagenesis, impairment of fertility
`13.2 Animal toxicology and /or pharmacology
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 General patient counseling
`
`FDA-approved patient labeling
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Adults
`Pediatric patients
`2.2
`2.3 Additional treatment after vomiting with Zmax
`2.4
`Instructions for the pharmacist
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1 Hypersensitivity reactions
`4.2 Cholestatic jaundice/hepatic dysfunction
`5 WARNINGS AND PRECAUTIONS
`5.1 Allergic and skin reactions
`5.2 Hepatotoxicity
`Clostridium difficile-associated diarrhea
`5.3
`Exacerbation of myasthenia gravis
`5.4
`5.5 QT Prolongation
`5.6 Gastrointestinal Disturbances
`5.7 Development of drug resistant bacteria
`ADVERSE REACTIONS
`6.1 Clinical trials experience
`6.2 Postmarketing experience with other azithromycin products
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`8.3 Nursing mothers
`8.4
`Pediatric use
`8.5 Geriatric use
`8.6 Renal impairment
`8.7 Gender
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of action
`12.2 Pharmacodynamics
`
`6
`
`7
`8
`
`Reference ID: 3389169
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`
`Zmax is indicated for the treatment with mild to moderate infections caused by susceptible isolates of
`the designated microorganisms in the specific conditions listed below. [See CLINICAL STUDIES
`(14)]
`
`Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis or
`Streptococcus pneumoniae.
`
`Community-acquired pneumonia in adults and pediatric patients six months of age or older due to
`Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus
`pneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based on
`extrapolation of adult efficacy. [See USE IN SPECIFIC POPULATIONS (8.4)]
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and other
`antibacterial drugs, Zmax 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.
`
`Appropriate culture and susceptibility tests should be performed before treatment to determine the
`causative organism and its susceptibility to Zmax. [See Clinical Pharmacology (12.4)] Therapy with
`
`Zmax may be initiated before results of these tests are known; once the results become available,
`antimicrobial therapy should be adjusted accordingly.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Adults
`Zmax should be taken as a single 2 g dose. Zmax provides a full course of antibacterial therapy in a
`single oral dose. It is recommended that Zmax be taken on an empty stomach (at least 1 hour before or
`2 hours following a meal).
`
`2.2 Pediatric patients
`
`For pediatric patients 6 months and older, Zmax should be taken as a single dose of 60 mg/kg
`(equivalent to 27 mg/lb) body weight. The Zmax dose in mL is equivalent to the child’s weight in lb
`(1 mL/lb dose, see Table 1 below), for a body weight of less than 75 lb (34 kg). It is recommended
`that Zmax be taken on an empty stomach (at least 1 hour before or 2 hours following a meal).
`
`Pediatric patients weighing 75 lb (34 kg) or more should receive the adult dose (2 g).
`
`Reference ID: 3389169
`
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`

`

`Table 1. Zmax Pediatric Dosage Guidelines: 1-dose regimen
`
`Dosing Calculated on 1 mL/lb,
`Dose 1 mL of Suspension for every 1 lb of Body Weight for
`Children <75 lb (34 kg)a
`1 mL/lb Dose
`
`Weight
`
`Lb
`
`Kg
`
`10
`15
`20
`25
`30
`35
`40
`45
`50
`55
`60
`65
`70
`>75
`
`5
`7
`9
`11
`14
`16
`18
`20
`23
`25
`27
`30
`32
`34
`
`Dose
`(mg)
`
`270
`405
`540
`675
`810
`945
`1080
`1215
`1350
`1485
`1620
`1755
`1890
`2000
`
`Volume
`(mL)
`
`10
`15
`20
`25
`30
`35
`40
`45
`50
`55
`60
`65
`70
`Consume entire contents of bottle
`
`a To ensure accurate dosing, a dosing spoon, medicine syringe, or cup is recommended.
`
`2.3 Additional treatment after vomiting with Zmax
`In the event that a patient vomits within 5 minutes of administration, the health care provider should
`consider additional antibiotic treatment since there would be minimal absorption of azithromycin.
`Since insufficient data exist on absorption of azithromycin if a patient vomits between 5 and 60
`minutes following administration, alternative therapy should be considered. Neither a second dose of
`Zmax nor alternative treatment is warranted if vomiting occurs 60 minutes following administration,
`in patients with normal gastric emptying. In patients with delayed gastric emptying, alternative
`therapy should be considered.
`
`Instructions for the pharmacist
`2.4
`Constitute with 60 mL of water and replace cap. Shake bottle well before dispensing. Do not
`refrigerate. Constituted suspension should be consumed within 12 hours.
`
`Reference ID: 3389169
`
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`

`

`For pediatric dosing in patients weighing less than 75 lb (34 kg), use of a dosing device is
`recommended. The pharmacist should inform the patient’s caregiver that any suspension remaining
`after dosing MUST be discarded.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`Each bottle of Zmax contains azithromycin dihydrate equivalent to 2 g of azithromycin. After
`constitution with 60 mL of water, each mL of suspension contains 27 mg of azithromycin. The
`suspension is a white or off-white color and has a cherry/banana flavor.
`
`4 CONTRAINDICATIONS
`
`4.1 Hypersensitivity reactions
`Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any
`macrolide or ketolide antibiotic.
`
`4.2 Cholestatic jaundice/hepatic dysfunction
`Zmax is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction
`associated with prior use of azithromycin.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Allergic and skin reactions
`Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome and toxic
`epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other
`formulations. Although rare, fatalities have been reported. 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. The relationship
`of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has
`not been determined.
`
`If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that
`reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
`
`5.2 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.
`
`5.3 Clostridium difficile-associated diarrhea
`Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial
`agents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment with
`antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
`
`C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin
`producing strains of C. difficile cause increased morbidity and mortality, as these infections can be
`
`3
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`Reference ID: 3389169
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`

`

`refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all
`patients who present with diarrhea following antibiotic use. Careful medical history is necessary since
`CDAD has been reported to occur over two months after the administration of antibacterial agents.
`
`If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to
`be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
`treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
`
`5.4 Exacerbation of myasthenia gravis
`Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been
`reported in patients receiving azithromycin therapy.
`
`5.5 QT Prolongation
`Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia
`and torsades de pointes, have been seen in treatment with macrolides, including azithromycin. Cases
`of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients
`receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal
`when weighing the risks and benefits of azithromycin for at-risk groups including:
`
`
`
`
`
`patients with known prolongation of the QT interval, a history of torsades de pointes,
`congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure
`patients on drugs known to prolong the QT interval
`patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or
`hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA
`(quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.
`
`Elderly patients may be more susceptible to drug-associated effects on the QT interval.
`
`5.6 Gastrointestinal Disturbances
`A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax was
`administered to a limited number of subjects with GFR< 10 mL/min [See USE IN SPECIFIC
`POPULATIONS (8.6)]
`
`Development of drug resistant bacteria
`5.7
`Prescribing Zmax 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.
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical studies experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
`in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
`and may not reflect the rates observed in practice.
`
`Reference ID: 3389169
`
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`
`

`

`Adults:
`
`The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single
`2 g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial
`sinusitis.
`
`In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions
`were gastrointestinal in nature and mild to moderate in severity.
`
`Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2 g
`dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%),
`and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for
`Zmax and 10% for pooled comparators.
`
`Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of <1%
`included the following:
`
`Cardiovascular: palpitations, chest pain
`Gastrointestinal: constipation, dyspepsia, flatulence, gastritis, oral moniliasis
`Genitourinary: vaginitis
`Nervous System: dizziness, vertigo
`General: asthenia
`Allergic: rash, pruritus, urticaria
`Special Senses: taste perversion
`
`Laboratory Abnormalities
`In subjects with normal baseline values, the following clinically significant laboratory abnormalities
`
`(irrespective of drug relationship) were reported in Zmax clinical trials:
`
`- with an incidence of greater than or equal to 1%: reduced lymphocytes and increased
`
`eosinophils; reduced bicarbonate;
`
`- with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN,
`
`creatinine, alterations in potassium.
`
`Where follow-up was provided, changes in laboratory tests appeared to be reversible.
`
`Pediatric Patients:
`The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3
`months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax.
`
`As in adults, the most common treatment-related adverse reactions in pediatric subjects were
`gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27
`mg/lb) of Zmax.
`
`In a study with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%)
`loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related
`gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an
`incidence greater than 1% began on the day of dosing in these subjects [43% (68/160)] and most [53%
`(84/160)] resolved within 48 hours of onset. Treatment-related adverse events that were not
`
`gastrointestinal, occurring with a frequency > 1% were: rash (5%), anorexia (2%), fever (2%), and
`dermatitis (2%).
`
`5
`
`Reference ID: 3389169
`
`

`

`In a second study of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported
`treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%),
`nausea (4%) and abdominal pain (4%).
`
`A third study investigated the tolerability of two different concentrations of azithromycin oral
`suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with
`azithromycin. The study evaluated the hypothesis that a more dilute, less viscous formulation (the
`recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children
`than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects
`taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not
`statistically different from the vomiting for the more concentrated suspension Across both treatment
`arms, the only treatment-related adverse events with a frequency of > 1% were vomiting (6%, 7/120)
`and diarrhea (2%, 2/120).
`
`Treatment-related adverse reactions with a frequency of < 1% following Zmax treatment in all 907
`
`pediatric subjects in the Phase 3 studies were:
`
`Body as a whole: chills, fever, flu syndrome, headache;
`
`Digestive: abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder,
`
`hepatitis;
`
`Hemic and Lymphatic: leukopenia;
`
`Nervous System: agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability,
`
`parasthesia, somnolence;
`
`Respiratory: asthma, bronchitis, cough increased, dyspnea, pharyngitis, rhinitis;
`
`Skin and Appendages: dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria;
`
`Special Senses: otitis media, taste perversion;
`
`Urogenital: dysuria.
`
`Laboratory Abnormalities
`In subjects with normal baseline values, the following clinically significant laboratory abnormalities
`(irrespective of drug relationship) were reported in Zmax pediatric clinical trials:
`- with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium;
`decreased lymphocytes; and alterations in neutrophils;
`- with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium;
`and alterations in sodium and glucose.
`
`Postmarketing experience with other azithromycin products
`6.2
`Because these reactions are reported voluntarily from a population of uncertain size, reliably
`estimating their frequency or establishing a causal relationship to drug exposure is not always possible.
`
`Adverse events reported with azithromycin immediate release formulations during the postmarketing
`period for which a causal relationship may not be established include:
`
`Allergic: arthralgia, edema, urticaria and angioedema
`Cardiovascular: palpitations and arrhythmias including ventricular tachycardia and hypotension
`There have been rare reports of QT prolongation and torsades de pointes.
`Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in
`dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports
`of tongue discoloration
`
`6
`
`Reference ID: 3389169
`
`

`

`General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal)
`Genitourinary: interstitial nephritis, acute renal failure, moniliasis and vaginitis
`Hematopoietic: thrombocytopenia, mild neutropenia
`Liver/Biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing
`experience with azithromycin. [See WARNINGS AND PRECAUTIONS (5.2)]
`Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness,
`agitation and syncope
`Psychiatric: aggressive reaction and anxiety
`Skin/Appendages: pruritus, rash, photosensitivity, rarely serious skin reactions including erythema
`multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
`Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus and rare reports of
`taste/smell perversion and/or loss
`
`7 DRUG INTERACTIONS
`
`Warfarin
`Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin
`time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest
`that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants.
`Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral
`anticoagulants concomitantly.
`
`8 USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and
`mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These
`daily doses in rats and mice, based on mg/m2, are estimated to be approximately equivalent to one or
`one-half of, respectively, the single adult oral dose of 2 g. In the animal studies, no evidence of harm
`to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled
`studies in pregnant women. Because animal reproduction studies are not always predictive of human
`response, azithromycin should be used during pregnancy only if clearly needed.
`
`Nursing Mothers
`8.3
`It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in
`human milk, caution should be exercised when azithromycin is administered to a nursing woman.
`
`Pediatric Use
`8.4
`Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been
`established.
`
`Community-Acquired Pneumonia: The safety and effectiveness of Zmax have been established in
`pediatric patients 6 months of age or older with community-acquired pneumonia due to Chlamydophila
`pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. Use of
`Zmax for these patients is supported by evidence from adequate and well-controlled studies of Zmax in
`adults with additional safety and pharmacokinetic data in pediatric patients. [See DOSAGE AND
`ADMINISTRATION (2.2), ADVERSE REACTIONS (6), CLINICAL PHARMACOLOGY (12.3)]
`
`7
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`

`

`Acute bacterial sinusitis: Safety and effectiveness in the treatment of pediatric patients with acute
`bacterial sinusitis have not been established.
`
`8.5 Geriatric Use
`Data collected from the azithromycin capsule and tablet formulations indicate that a dosage adjustment
`does not appear to be necessary for older patients with normal renal function (for their age) and hepatic
`function receiving treatment with Zmax.
`
`In clinical trials of Zmax, 17% of subjects were at least 65 years of age (214/1292) and 5% of subjects
`(59/1292) were at least 75 years of age. No overall differences in safety or effectiveness were observed
`between these subjects and younger subjects. Elderly patients may be more susceptible to
`
`development of torsades de pointes arrhythmia than younger patients. [See WARNINGS AND
`PRECAUTIONS (5.5)].
`
`Renal Impairment
`8.6
`No dosage adjustment is recommended for patients GFR >10 mL/min. Caution should be exercised
`when Zmax is administered to patients with GFR <10 mL/min, due to a higher incidence of
`gastrointestinal adverse events (8 of 19 subjects) observed in a limited number of subjects with GFR
`<10 mL/min. [See CLINICAL PHARMACOLOGY (12)]
`
`8.7 Gender
`The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax.
`However, previous studies have demonstrated no significant differences in the disposition of
`azithromycin between male and female subjects. No dosage adjustment of Zmax is recommended
`based on gender.
`
`10
`
`OVERDOSAGE
`
`Adverse events experienced in higher than recommended doses were similar to those seen at normal
`doses. In the event of overdosage, general symptomatic and supportive measures are indicated as
`required.
`
`11
`
`DESCRIPTION
`
`Zmax (azithromycin extended release) for oral suspension contains the active ingredient azithromycin
`(as azithromycin dihydrate), an azalide, a subclass of macrolide antibiotics. Azithromycin has the
`chemical name
`(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl--L-ribo-hexopyra
`nosyl) oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-
`(dimethylamino)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is
`derived from erythromycin; however, it differs chemically from erythromycin in that a
`methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is
`C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula:
`
`Reference ID: 3389169
`
`8
`
`

`

`CH3
`
`OH
`CH3
`
`HO
`
`O
`
`H3C
`
`CH3
`
`N
`
`O
`
`CH3
`
`CH3
`
`O
`
`CH3
`
`O
`
`CH3
`
`OH
`
`H3C
`N
`
`H3C
`
`HO
`
`HO
`
`H3C
`
`O
`
`CH3
`
`O
`
`O
`CH3 CH3
`Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of
`C38H72N2O122H2O and a molecular weight of 785.0.
`
`Zmax is a single-dose, extended release formulation of microspheres for oral suspension containing
`azithromycin (as azithromycin dihydrate) and the following excipients: glyceryl behenate, poloxamer
`407, sucrose, sodium phosphate tribasic anhydrous, magnesium hydroxide, hydroxypropyl cellulose,
`xanthan gum, colloidal silicon dioxide, titanium dioxide, artificial cherry flavor, and artificial banana
`flavor.
`
`Note: Each bottle of Zmax 2 g for oral suspension contains approximately 148 mg of sodium and 19 g
`of sucrose. Constituted Zmax oral suspension contains approximately 2 mg/mL of sodium and 0.26
`g/mL of sucrose.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Azithromycin is an antimicrobial agent [See Clinical Pharmacology (12.4)]
`
`12.2 Pharmacodynamics
`Cardiac Electrophysiology
`QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial
`in 116 healthy subjects who received either chloroquine (1000 mg) alone or in
`combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration
`of azithromycin increased the QTc interval in a dose- and concentration-dependent
`manner. In comparison to chloroquine alone, the maximum mean (95% 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.
`
`12.3 Pharmacokinetics
`Zmax is an extended release microsphere formulation. Based on data obtained from studies evaluating
`the pharmacokinetics of azithromycin in healthy adult subjects a higher peak serum concentration
`(Cmax) and greater systemic exposure (AUC 0-24) of azithromycin are achieved on the day of dosing
`following a single 2 g dose of Zmax versus 1.5 g of azithromycin tablets administered over 3 days (500
`
`9
`
`Reference ID: 3389169
`
`

`

`mg/day) or 5 days (500 mg on day 1, 250 mg/day on days 2-5) [Table 2]. Consequently, due to these
`different pharmacokinetic profiles, Zmax is not interchangeable with azithromycin tablet 3-day and 5-
`day dosing regimens.
`
`Table 2. Mean (SD) Pharmacokinetic Parameters for Azithromycin on Day 1 Following the
`Administration of a Single Dose of 2 g Zmax or 1.5 g of Azithromycin Tablets Given over 3 Days
`(500 mg/day) or 5 Days (500 mg on Day 1 and 250 mg on Days 2-5) to Healthy Adult Subjects
`
`Cmax (µg/mL)
`
`Pharmacokinetic
`Parameter*
`
`Azithromycin Regimen
`Zmax
`3-day ‡
`5-day ‡
`[N=41]†
`[N=12]
`[N=12]
`0.821
`0.441
`0.434
`(0.281)
`(0.223)
`(0.202)
`5.0
`2.5
`2.5
`
`Tmax § (hr)
`(2.0-8.0)
`(1.0-4.0)
`(1.0-6.0)
`8.62
`2.58
`2.60
`AUC0-24
`
`(2.34)
`(0.84)
`(0.71)
`(µg·hr/mL)
`20.0
`17.4
`14.9
`
` AUC0-∞¶
`(6.66)
`(6.2)
`(3.1)
`(µg·hr/mL)
`58.8
`71.8
`68.9
`t1/2 (hr)
`(6.91)
`(14.7)
`(13.8)
`* Zmax, 3-day and 5-day regimen parameters obtained from separate pharmacokinetic studies
`† N = 21 for AUC0-∞ and t1/2
`
`‡ Cmax, Tmax and AUC0-24 values for Day 1 only
`
`§ Median (range)
`
`¶ Total AUC for the 1-day, 3-day and 5-day regimens
`
`SD = standard deviation
`
`Cmax = maximum serum concentration
`
`Tmax = time to Cmax
`
`AUC = area under concentration vs. time curve
`
`t1/2 = terminal serum half-life
`
`
`Absorption
`The bioavailability of Zmax relative to azithromycin immediate release (IR) (powder for oral
`suspension) was 83%. On average, peak serum concentrations were achieved approximately 2.5 hours
`later following Zmax administration and were lower by 57%, compared to 2 g azithromycin IR. Thus,
`single 2 g doses of Zmax and azithromycin IR are not bioequivalent and are not interchangeable.
`
`Effect of food on absorption: A high-fat meal increased the rate and extent of absorption of a 2 g dose
`of Zmax (115% increase in Cmax, and 23% increase in AUC0-72) compared to the fasted state. A
`standard meal also increased the rate of absorption (119% increase in Cmax) and with less effect on the
`extent of absorption (12% increase in AUC0-72) compared to administration of a 2 g Zmax dose in the
`fasted state.
`
`Effect of antacids: Following the administration of Zmax with an aluminum and magnesium hydroxide
`antacid, the rate and extent of azithromycin absorption were not altered.
`
`Reference ID: 3389169
`
`10
`
`

`

`Distribution
`The serum protein binding of azithromycin is concentration dependent, decreasing from 51% at
`0.02 g/mL to 7% at 2 g/mL. Following oral administration, azithromycin is widely distributed
`
`throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg.
`
`Azithromycin concentrates in fibroblasts, epithelial cells, macrophages, and circulating neutrophils and
`monocytes. Higher azithromycin concentrations in tissues than in plasma or serum have been
`observed. White blood cell and lung exposure data in humans following a single 2 g dose of Zmax in
`adults are shown in Table 3. Following a 2 g single dose of Zmax, azithromycin achieved higher
`exposure (AUC0-120) in mononuclear leukocytes (MNL) and polymorphonuclear leukocytes (PMNL)
`than in serum. The azithromycin exposure (AUC0-72) in lung tissue and alveolar cells (AC) was
`approximately 100 times that in serum; and the exposure in epithelial lining fluid (ELF) was also
`higher (approximately 2-3 times) than in serum. The clinical significance of this distribution data is
`unknown.
`
`Table 3. Azithromycin Exposure Data in White Blood Cells and Lung Following a 2 g Single
`Dose of Zmax in Adults
`
`WBC
`MNL‡
`
`PMNL‡
`
`LUNG
`
`ALVEOLAR CELL¶
`ELF¶
`
`
`
`Cmax (µg/mL)
`116 (40.2)
`146 (66.0)
`
`A single 2 g dose of Zmax
`AUC0-24 (µg·hr/mL)
`AUC0-120 (µg·hr/mL)
`1790 (540)
`4710 (1100)
`2080 (650)
`10000 (2690)
`
`† (µg/mL)
`Ct=120
`16.2 (5.51)
`81.7 (23.3)
`
`Cmax (µg/mL)
`669
`
`AUC0-24 (µg·hr/mL)
`7028
`
`AUC0-72 (µg·hr/mL)
`20403
`
`3.2
`
`17.6
`
`131
`
`-
`
`-
`
`Cmax (µg/g)
`AUC0-72 (µg·hr/g)
`AUC0-24 (µg·hr/g)
`-
`1693
`505
`37.9
`LUNG TISSUE¶
`
`Abbreviation: WBC: white blood cells; MNL: mononuclear leukocytes; PMNL: polymorphonuclear leukocytes; ELF:
`Epithelial lining fluid
`† Azithromycin concentration at 120 hours after the start of dosing
`
`‡ Data are presented as mean (standard deviation)
`
`¶ Cmax and AUC were calculated based on composite profile (n = 4 subjects/time point/formulation).
`
`
`Following a regimen of 500 mg of azithromycin tablets on the first day and 250 mg daily for 4 days,
`
`only very low concentrations were noted in cerebrospinal fluid (less than 0.01 g/mL) in the presence
`
`of non-inflamed meninges.
`
`Metabolism
`
`In vitro and in vivo studies to assess the metabolism of