• Hepatotoxicity: severe, and sometimes fatal, hepatotoxicity has been
`
`
`
`reported. Discontinue immediately if signs and symptoms of hepatitis
`
`
`occur. (5.2)
`
`• Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of
`
`
`
`
`
`
`azithromycin in neonates (treatment up to 42 days of life), IHPS has been
`
`
`
`
`
`
`reported. Direct parents and caregivers to contact their physician if
`
`
`
`
`
`vomiting or irritability with feeding occurs. (5.3)
`
`• Prolongation of the QT interval and cases of torsades de pointes have been
`
`
`
`
`reported. This risk which can be fatal should be considered in patients with
`
`
`
`
`
`certain cardiovascular disorders including known QT prolongation or
`
`history of torsades de pointes, those with proarrhythmic conditions, and
`
`
`
`with other drugs that prolong the QT interval. (5.4)
`
`
`• Clostridium difficile-Associated Diarrhea: Evaluate patients if diarrhea
`
`
`
`occurs. (5.5)
`
`• Zmax may exacerbate muscle weakness in persons with myasthenia gravis.
`
`
`
`
`(5.6)
`
`• Gastrointestinal Disturbances: higher incidence in patients with
`
`
`
`
`GFR<10 mL/min. (5.7)
`
`
`
`
`------------------------------ 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------------------------------­
`
`
`
`• Nelfinavir: Close monitoring for known adverse reactions of azithromycin,
`
`
`
`such as liver enzyme abnormalities and hearing impairment, is warranted.
`
`
`
`
`(7.1)
`
`• Warfarin: Use with azithromycin may increase coagulation times; monitor
`
`
`prothrombin time. (7.2)
`
`
`
`
`----------------------- 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)
`
`
`
`• Geriatric use: Elderly patients may be more susceptible to development of
`
`
`
`
`torsades de pointes arrhythmias. (8.5)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling.
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS---------------------­
`
`
`
`
`Bottle containing 2 g azithromycin for constitution with 60 mL of water (final
`
`
`
`
`
`
`concentration 27 mg/mL). (3)
`
`
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------­
`
`
`
`
`Hypersensitivity to azithromycin, erythromycin, or any macrolide or ketolide
`
`
`drug. (4.1)
`
`
`
`History of cholestatic jaundice/hepatic dysfunction associated with prior use
`
`
`
`
`
`
`of azithromycin. (4.2)
`
`
`
`
`----------------------- WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`• Allergic and Skin Reactions (including fatal): Discontinue Zmax if reaction
`
`
`
`
`occurs. (5.1)
`
`Revised: 4/2019
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Acute Bacterial Sinusitis in Adults and Community-Acquired
`
`
`
`
`
`Pneumonia
`
`1.2 Limitations of Use
`
`
`1.3 Usage
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Adults
`
`
`2.2
`Pediatric Patients
`
`
`
`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
`
`
`5.3
`Infantile Hypertrophic Pyloric Stenosis
`
`
`
`
`
`5.4 QT Prolongation
`
`
`5.5 Clostridium difficile-Associated Diarrhea
`
`
`
`5.6 Exacerbation of Myasthenia Gravis
`
`
`
`5.7 Gastrointestinal Disturbances
`
`
`5.8 Development of Drug Resistant Bacteria
`
`
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2
`Postmarketing Experience with Other Azithromycin Products
`
`
`
`
`
`
`
`
`6.3 Laboratory Abnormalities
`
`
`
` 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
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`
`
`
`Zmax is a macrolide antimicrobial drug indicated for mild to moderate
`
`
`
`infections caused by designated, susceptible bacteria:
`
`
`
`• Acute bacterial sinusitis in adults (1.1)
`
`
`
`
`
`• Community-acquired pneumonia in adults and pediatric patients 6 months
`
`
`and older. (1.1)
`
`
`
`
`Limitations of Use
`Azithromycin should not be used in patients with pneumonia who are judged
`
`
`
`
`to be inappropriate for oral therapy because of moderate to severe illness or
`
`risk factors (1.2).
`
`
`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. (1.3)
`
`
`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
`
`
`
`
`• Adults: 2 g as a single dose; consume contents of full bottle. (2.1)
`
`
`
`
`
`• Pediatric patients (6 months and older): 60 mg/kg as a single dose, up to a
`
`
`
`
`
`
`maximum of 2 g. (2.2)
`
`
`
`
`2
`
`
`3
`
`4
`
`
`6
`
`
`7
`
`
`8
`
`
`DRUG INTERACTIONS
`
`7.1 Nelfinavir
`
`
`7.2 Warfarin
`
`
`7.3
`Potential Drug-Drug Interaction with Macrolides
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`8.2
`Lactation
`
`
`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
`
`
`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
`
`
`14.1 Acute Bacterial Maxillary Sinusitis
`
`
`
`
`
`14.2 Community-Acquired Pneumonia
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`
`
`Reference ID: 4423479
`
`
`
` 1
`
`

`

`
`
`
`
` INDICATIONS AND USAGE
`
`
` FULL PRESCRIBING INFORMATION
`
`
` 1
`
`
`
`
`
`Acute Bacterial Sinusitis in Adults and Community-Acquired Pneumonia
`1.1
`
`
`
`
`
`
`Zmax (azithromycin) is a macrolide antibacterial drug indicated for the treatment of patients with mild
`
`
`
`to moderate infections caused by susceptible strains 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)]
`
`
`
`Limitations of Use
`1.2
`
`
`Zmax is not recommended for use in patients with pneumonia who are judged to be inappropriate for
`
`
`
`
`
`oral therapy because of moderate to severe illness or risk factors such as any of the following:
`
`
`• patients with cystic fibrosis,
`
`
`• patients with nosocomial infections,
`
`
`• patients with known or suspected bacteremia,
`
`
`• patients requiring hospitalization,
`
`
`• elderly or debilitated patients, or
`
`
`• patients with significant underlying health problems that may compromise their ability to
`
`
`respond to their illness (including immunodeficiency or functional asplenia).
`
`
`
`
`Usage
`1.3
`
`
`To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax
`
`
`(azithromycin) and other antibacterial drugs, Zmax (azithromycin) 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.
`
`
`
`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 hr before or
`
`
`2 hr 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 body
`
`weight for patients weighing less than 34 kg. It is recommended that Zmax be taken on an empty
`
`
`
`
`
`stomach (at least 1 hr before or 2 hrs following a meal).
`
`
`
`
`
`
`
`
`Reference ID: 4423479
`
`
`
` 1
`
`

`

`
`
`
`
`
`
`
` Pediatric patients weighing 34 kg should receive the adult dose (2 g).
`
`
`
`
` Table 1. Zmax Pediatric Dosage Guidelines: 1-dose regimen
`
`
`
`
`
` Dosing Calculated on 60 mg/kg as a single dose for
` Children <34 kga
`
`
`
`
`
`
`
`
`
` Weight
`
` Kg
`
`
` 5
`
` 7
`
` 9
`
` 11
`
` 14
`
` 16
`
` 18
`
` 20
`
` 23
`
` 25
`
` 27
`
` 30
`
` 32
` >34
`
`
`
`
` 27 mg/mL Dose
`
`
`
`
`
`
` 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 hr.
`
`
`
`
`For pediatric dosing in patients weighing less than 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.
`
`
`
`
`
`
`
`
`
`Reference ID: 4423479
`
`
`
` 2
`
`

`

`
`
`
`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 drug.
`
`
`
`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, Acute Generalized Exanthematous
`
`
`Pustulosis (AGEP), Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported in
`
`
`patients on azithromycin therapy using other formulations. Fatalities have been reported. Cases of
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also 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 Infantile Hypertrophic Pyloric Stenosis (IHPS)
`
`Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been
`
`
`reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding
`
`occurs.
`
`
`
`
`Reference ID: 4423479
`
`
`
` 3
`
`

`

`
`5.4 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.
`
`
`
`5.5 Clostridium difficile-Associated Diarrhea (CDAD)
`
`
`
`
`
`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
`
`
`
`
`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.
`
`
`
`
`
`5.6 Exacerbation of Myasthenia Gravis
`
`
`
`Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been
`
`
`
`
`reported in patients receiving azithromycin therapy.
`
`
`5.7 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)]
`
`5.8 Development of Drug Resistant Bacteria
`
`
`
`
`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.
`
`
`
`
`
`
`Reference ID: 4423479
`
`
`
` 4
`
`

`

`
`
`
`
`
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`6.1 Clinical Trials 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.
`
`
`
`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
`
`
`
`
`
` 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 of Zmax.
`
`
`
`
`
`In a trial 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 hr 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%).
`
`
`
`
`
`
`In a second trial 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%).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4423479
`
`
`
` 5
`
`

`

`
`
`
`
` A third trial 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;
`
`
`Hematologic and lymphatic: Leukopenia;
`
`
`
`Nervous system: Agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability,
`
`
`
`
`paresthesia, Somnolence;
`
`
`
`Respiratory: Asthma, bronchitis, cough, dyspnea, pharyngitis, rhinitis;
`
`
`
`Skin and appendages: Dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria;
`
`
`Special senses: Otitis media, taste perversion;
`
`
`
`
`Urogenital: Dysuria.
`
`
`
`
`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 reports of QT prolongation and torsades de pointes.
`
`
`Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous
`
`
`
`colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration.
`
`
`
`
`
`General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis.
`
`
`
`Genitourinary: Interstitial nephritis, acute renal failure 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, serious skin reactions including erythema
`
`
`
`
`multiforme, AGEP, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS.
`
`
`
`
`Special senses: Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of
`
`
`
`
`
`taste/smell perversion and/or loss.
`
`
`
`
`
`
`
`
`
`Reference ID: 4423479
`
`
`
` 6
`
`

`

`
`
`Pregnancy
`
`
`
`
`
` Laboratory Abnormalities
` 6.3
`
`
` In subjects with normal baseline values, the following clinically significant laboratory abnormalities
`
`
`
` (irrespective of drug relationship) were reported in Zmax clinical trials in adults and pediatric patients:
`
`
`Adults:
`
`
`
`
`
`Laboratory abnormalities with an incidence of greater than or equal to 1%: reduced lymphocytes and
`
`increased eosinophils; reduced bicarbonate. Laboratory abnormalities 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:
`
`
`
`
`Laboratory abnormalities 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.
`
`
`7 DRUG INTERACTIONS
`
`
`
`Nelfinavir
`7.1
`
`
`Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in
`
`
`increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not
`
`
`recommended when administered in combination with nelfinavir, close monitoring for known adverse
`
`reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted.
`
`
`[see Adverse Reactions (6)]
`
`
`7.2 Warfarin
`
`
`Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may
`
`potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not
`
`
`
`affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times
`
`should be carefully monitored while patients are receiving azithromycin and oral anticoagulants
`
`concomitantly.
`
`
`Potential Drug-Drug Interaction with Macrolides
`7.3
`
`
`Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with
`
`azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug
`
`interaction. However, drug interactions have been observed with other macrolide products. Until
`
`further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used
`
`with azithromycin careful monitoring of patients is advised.
`
`
`8
`
`
`8.1
`
`
`Risk Summary
`
`Available data from published literature and postmarketing experience over several decades with
`
`
`
`azithromycin use in pregnant women have not identified any drug-associated risks for major birth
`defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies
`
`
`with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at doses up to
`
`
`
` 7
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`
`Reference ID: 4423479
`
`

`

`
`
`
`1, 0.5, and 0.4 times, respectively, an adult human oral dose of 2 g based on body surface area.
`
`
`
` Decreased viability and delayed development were observed in the offspring of pregnant rats
` administered azithromycin from day 6 of pregnancy through weaning at a dose equivalent to an adult
`
`
`
` human oral dose of 2 g based on body surface area (see Data).
`
`
`
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated populations is
`
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In
`
`
`the U.S. general population, the estimated background risk of major birth defects and miscarriage in
`
`
`clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
`
`
`Data
`
`Human Data
`
`Available data from published observational studies, case series, and case reports over several decades
`
`do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal
`
`
`outcomes with azithromycin use in pregnant women. Limitations of these data include the lack of
`
`randomization and inability to control for confounders such as underlying maternal disease and
`
`
`maternal use of concomitant medications.
`
`
`
`Animal Data
`
`Azithromycin administered during the period of organogenesis did not cause fetal malformations in
`
`rats and mice at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface
`
`
`
`
`area, this dose is approximately equivalent to one or one-half of, respectively, the single adult human
`
`
`
`oral dose of 2 g. In rabbits administered azithromycin at oral doses of 10, 20, and 40 mg/kg/day during
`
`
`
`
`
`organogenesis, reduced maternal body weight and food consumption were observed in all groups; no
`
`evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is estimated
`
`
`to be 0.4 times an adult human oral dose of 2 g based on body surface area.
`
`
`
`In a pre- and postnatal development study, azithromycin was administered orally to pregnant rats from
`
`
`
`
`day 6 of pregnancy until weaning at doses of 50 or 200 mg/kg/day. Maternal toxicity (reduced food
`
`
`consumption and body weight gain; increased stress at parturition) was observed at the higher dose.
`
`
`Effects in the offspring were noted at 200 mg/kg/day during the postnatal development period
`(decreased viability, delayed developmental landmarks). These effects were not observed in a pre- and
`
`
`postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day 15 of
`
`
`pregnancy until weaning.
`
`
`8.2
`
`
`Risk Summary
`
`Azithromycin is present in human milk (see Data). Non-serious adverse reactions have been reported
`
`
`in breastfed infants after maternal administration of azithromycin (see Clinical Considerations). There
`
`are no available data on the effects of azithromycin on milk production. The developmental and health
`
`benefits of breastfeeding should be considered along with the mother’s clinical need for Zmax and any
`
`
`
`
`potential adverse effects on the breastfed infant from Zmax or from the underlying maternal condition.
`
`
`
`
`
`Clinical Considerations
`
`
`Advise women to monitor the breastfed infant for diarrhea, vomiting, or rash.
`
`
`
`
`
`Lactation
`
`
`
`
`Reference ID: 4423479
`
`
`
` 8
`
`
`
`

`

`
`
`
`
`
`
`
` Data
`
`
`
`
` Azithromycin breastmilk concentrations were measured in 20 women after receiving a single 2 g oral
` dose of azithromycin during labor. Breastmilk samples collected on days 3 and 6 postpartum as well as
`
` 2 and 4 weeks postpartum revealed the presence of azithromycin in breastmilk up to 4 weeks after
`
`
`dosing. In another study, a single dose of azithromycin 500 mg was administered intravenously to
`8 women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12
`
`
`and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours.
`
`
` 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)]
`
`
`
`
`
`
` 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 (5.4)]
`
`
`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