Azithromycin: Package Insert and Label Information

AZITHROMYCIN- azithromycin dihydrate tablet, film coated
Carlsbad Technology, Inc.

1 Indications and Usage

Azithromycin film coated tablets are 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.
1.1 Sexually Transmitted Diseases
Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis
1.2 Mycobacterial Infections
Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease
Azithromycin film coated tablets, taken alone or in combination with rifabutin at its approved
dose, is indicated for the prevention of disseminated MAC disease in persons with advanced
HIV infection [see Dosage and Administration (2)].
Treatment of Disseminated MAC Disease
Azithromycin film coated tablets, taken in combination with ethambutol, is indicated for the
treatment of disseminated MAC infections in persons with advanced HIV infection [see Use in
Specific Populations (8.4) and Clinical Studies (14.1)].
1.3 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
azithromycin film coated tablets and other antibacterial drugs, azithromycin film coated
tablets 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

[see Indications and Usage (1)]
2.1 Sexually Transmitted Diseases
The recommended dose of azithromycin film coated tablets for the treatment of nongonococcal
urethritis and cervicitis due to C. trachomatis is a single 1 gram (1000 mg) dose of
2.2 Mycobacterial Infections
Prevention of Disseminated MAC Infections
The recommended dose of azithromycin for the prevention of disseminated Mycobacterium
avium complex (MAC) disease is: 1,200 mg taken once weekly. This dose of azithromycin may
be combined with the approved dosage regimen of rifabutin.
Treatment of Disseminated MAC Infections
Azithromycin should be taken at a daily dose of 600 mg, in combination with ethambutol at
the recommended daily dose of 15 mg/kg. Other antimycobacterial drugs that have shown in
vitro activity against MAC may be added to the regimen of azithromycin plus ethambutol at the
discretion of the physician or health care provider.

3 Dosage Forms and Strength

Azithromycin Tablets USP, 600 mg (debossed “YSP257” on one side and plain on the reverse side)
are supplied as white to off-white film-coated tablets containing azithromycin dihydrate equivalent
to 600 mg azithromycin. These are packaged in bottles of 30 tablets.

4 Contraindications

4.1 Hypersensitivity
Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin,
erythromycin, any macrolide, or ketolide drug.
4.2 Hepatic Dysfunction
Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic
dysfunction associated with prior use of azithromycin.

5 Warnings and Precautions

5.1 Hypersensitivity
Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions
including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome,
and toxic epidermal necrolysis, have been reported rarely in patients on azithromycin therapy.
[see Contraindications (4.1)]
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
prolonged exposure to antigen is presently unknown.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should
be instituted. Physicians should be aware that allergic symptoms may reappear 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.
5.4 QT Prolongation
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac
arrhythmia and torsades de pointes, have been seen with 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
Elderly patients may be more susceptible to drug-associated effects on the QT interval.
5.5 Clostridium difficile-Associated Diarrhea (CDAD)
CDAD has been reported with use of nearly all antibacterial agents, including azithromycin,
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 antibacterial 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
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome
have been reported in patients receiving azithromycin therapy.
5.7 Use in Sexually Transmitted Infections
Azithromycin, at the recommended dose, should not be relied upon to treat gonorrhea or
syphilis. Antibacterial agents used in high doses for short periods of time to treat nongonococcal
urethritis may mask or delay the symptoms of incubating gonorrhea or syphilis.
All patients with sexually transmitted urethritis or cervicitis should have a serologic test for
syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis.
Appropriate antibacterial therapy and follow-up tests for these diseases should be initiated if
infection is confirmed.
5.8 Development of Drug-Resistant Bacteria
Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection
or a prophylactic indication 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 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.
In clinical trials, most of the reported adverse reactions were mild to moderate in severity and
were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from
the multiple-dose clinical trials discontinued azithromycin therapy because of treatmentrelated
adverse reactions. Serious adverse reactions included angioedema and cholestatic
jaundice. Most of the adverse reactions leading to discontinuation were related to the
gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. [see Clinical Studies
Multiple-dose regimen
Overall, the most common adverse reactions in adult patients receiving a multiple-dose
regimen of azithromycin were related to the gastrointestinal system with diarrhea/loose
stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported.
No other adverse reactions occurred in patients on the multiple-dose regimen of azithromycin
with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1%
or less included the following:
Cardiovascular: Palpitations and chest pain.
Gastrointestinal: Dyspepsia, flatulence, vomiting, melena, and cholestatic jaundice.
Genitourinary: Monilia, vaginitis, and nephritis.
Nervous System: Dizziness, headache, vertigo, and somnolence.
General: Fatigue.
Allergic: Rash, photosensitivity, and angioedema.
Chronic therapy with 1200 mg weekly regimen
The nature of adverse reactions seen with the 1200 mg weekly dosing regimen for the
prevention of Mycobacterium avium infection in severely immunocompromised HIV-infected
patients were similar to those seen with short-term dosing regimens. [see Clinical Studies (14)]
Chronic therapy with 600 mg daily regimen combined with ethambutol
The nature of adverse reactions seen with the 600 mg daily dosing regimen for the treatment
of Mycobacterium avium complex infection in severely immunocompromised HIV-infected
patients were similar to those seen with short term dosing regimens. Five percent of patients
experienced reversible hearing impairment in the pivotal clinical trial for the treatment of
disseminated MAC in patients with AIDS. Hearing impairment has been reported with
macrolide antibiotics, especially at higher doses. Other treatment-related adverse reactions
occurring in >5% of subjects and seen at any time during a median of 87.5 days of therapy
include: abdominal pain (14%), nausea (14%), vomiting (13%), diarrhea (12%), flatulence
(5%), headache (5%), and abnormal vision (5%). Discontinuations from treatment due to

laboratory abnormalities or adverse reactions considered related to study drug occurred in 8
of 88 (9.1%) of subjects.
Single 1 gram dose regimen
Overall, the most common adverse reactions in patients receiving a single-dose regimen of 1
gram of azithromycin were related to the gastrointestinal system and were more frequently
reported than in patients receiving the multiple-dose regimen.
Adverse reactions that occurred in patients on the single 1 gram dosing regimen of
azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea
(5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of azithromycin.
Because these reactions are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to drug
Adverse reactions reported with azithromycin during the postmarketing period in adult and/or
pediatric patients for which a causal relationship may not be established include:
Allergic: Arthralgia, edema, urticaria, and angioedema.
Cardiovascular: 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 tongue discoloration.
General: Asthenia, paresthesia, fatigue, malaise, and anaphylaxis
Genitourinary: Interstitial nephritis, acute renal failure, and vaginitis.
Hematopoietic: Thrombocytopenia.
Liver/Biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and
hepatic failure. [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, and 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.
6.3 Laboratory Abnormalities
Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials
were reported as follows:
● With an incidence of 1-2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT),
GGT, and AST (SGOT).
● With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count,
elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and
When follow-up was provided, changes in laboratory tests appeared to be reversible.
In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued
therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal
function abnormality.
In a phase 1 drug interaction study performed in normal volunteers, 1 of 6 subjects given the
combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone, and 0 of 6 given
azithromycin alone developed a clinically significant neutropenia (<500 cells/mm3).
Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium
avium disease in severely immunocompromised HIV-infected patients. [see Clinical Studies (14)]
Chronic therapy (median duration: 87.5 days, range: 1-229 days) that resulted in laboratory
abnormalities in >5% of subjects with normal baseline values in the pivotal trial for treatment
of disseminated MAC in severely immunocompromised HIV-infected patients treated with
azithromycin 600 mg daily in combination with ethambutol include: a reduction in absolute
neutrophils to <50% of the lower limit of normal (10/52, 19%) and an increase to five times
the upper limit of normal in alkaline phosphatase (3/35, 9%). These findings in subjects with
normal baseline values are similar when compared to all subjects for analyses of neutrophil
reductions (22/75, 29%) and elevated alkaline phosphatase (16/80, 20%). Causality of these
laboratory abnormalities due to the use of study drug has not been established.

7 Drug Interactions

7.1 Nelfinavir
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.
7.3 Potential Drug-Drug Interaction with Macrolides
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.

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