AZITHROMYCIN MONOHYDRATE- azithromycin monohydrate tablet

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
AZITHROMYCIN MONOHYDRATE (UNII: JTE4MNN1MD) (AZITHROMYCIN ANHYDROUS - UNII:J2KLZ20U1M)
Available from:
LUPIN LIMITED
INN (International Name):
AZITHROMYCIN MONOHYDRATE
Composition:
AZITHROMYCIN ANHYDROUS 600 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets USP and other antibacterial drugs, azithromycin tablets 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. Azithromycin tablets USP 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. Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease Azithromycin tablets USP, taken alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated MAC disease in persons with ad
Product summary:
Azithromycin Tablets USP, 600 mg are supplied as white, oval shaped film-coated tablets, engraved with "LU" on one side and "L13" on the other side containing azithromycin monohydrate USP equivalent to 600 mg of azithromycin USP. These are packaged in bottles of 30 tablets as follows: Bottles of 30 Tablets:   NDC 68180-162-06 Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
57297-162-06

AZITHROMYCIN MONOHYDRATE- azithromycin monohydrate tablet

LUPIN LIMITED

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use azithromycin tablets USP safely and

effectively. See full prescribing information for azithromycin tablets USP.

AZITHROMYCIN tablets USP, 600 mg, for oral use

Initial U.S. Approval: 1991

RECENT MAJOR CHANGES

INDICATIONS AND USAGE

Azithromycin tablets USP are a macrolide antibacterial indicated for mild to moderate infections caused by designated,

susceptible bacteria:

Mycobacterial Infections (1.2)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets

USP and other antibacterial drugs, azithromycin tablets USP should be used only to treat or prevent infections

that are proven or strongly suspected to be caused by susceptible bacteria.

DOSAGE AND ADMINISTRATION

Mycobacterial Infections (2.2)

DOSAGE FORMS AND STRENGTHS

Azithromycin tablets USP, 600 mg

CONTRAINDICATIONS

Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide antibiotic. (4.1)

Patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. (4.2)

WARNINGS AND PRECAUTIONS

Serious (including fatal) allergic and skin reactions. Discontinue azithromycin and initiate appropriate therapy if

reaction occurs. (5.1)

Hepatotoxicity: Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. (5.2)

Prolongation of 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 torsades de

pointes, those with prorrhythmic conditions, and with other drugs that prolong the QT interval. (5.3)

Clostridium difficile -associated diarrhea: Evaluate patients if diarrhea occurs. (5.4)

Azithromycin exacerbate muscle weakness in persons with myasthenia gravis (5.5)

ADVERSE REACTIONS

The most common adverse reactions are diarrhea (5%), nausea (3%), abdominal pain (3%), or vomiting, (no percent

given). (6)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Nelfinavir: Close monitoring for known side effects 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 effectiveness 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.

Revised: 2/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.2 Mycobacterial Infections

2 DOSAGE AND ADMINISTRATION

2.2 Mycobacterial Infections

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Hepatic Dysfunction

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

5.2 Hepatotoxicity

5.3 QT Prolongation

5.4 Clostridium difficile-Associated Diarrhea (CDAD)

5.5 Exacerbation of Myasthenia Gravis

5.7 Development of Drug-Resistant Bacteria

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-marketing Experience

6.3 Laboratory Abnormalities

7 DRUG INTERACTIONS

7.1 Nelfinavir

7.2 Warfarin

7.3 Potential Drug-Drug Interaction with Macrolides

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

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

14 CLINICAL STUDIES

14.1 Clinical Studies in Patients with Advanced HIV Infection for the Prevention and Treatment of

Disease Due to Disseminated Mycobacterium Avium Complex (MAC)

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin

tablets USP and other antibacterial drugs, azithromycin tablets 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.

Azithromycin tablets USP 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.

1.2 Mycobacterial Infections

Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease

Azithromycin tablets USP, 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 tablets USP, 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)].

2 DOSAGE AND ADMINISTRATION

[see INDICATIONS AND USAGE (1)]

Azithromycin tablets USP can be taken with or without food. However, increased tolerability has been

observed when tablets are taken with food.

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: 1200 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 STRENGTHS

Azithromycin Tablets USP, 600 mg are supplied as white, oval shaped film-coated tablets, engraved

with "LU" on one side and "L13" on the other side containing azithromycin monohydrate USP equivalent

to 600 mg of azithromycin USP. 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

Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported rarely in patients on

azithromycin therapy. [see CONTRAINDICATIONS (4.1)].

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 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 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:

Sections or subsections omitted from the full prescribing information are not listed.

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.

5.4 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.

5.5 Exacerbation of Myasthenia Gravis

Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been

reported in patients receiving azitrhromycin therapy.

5.7 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 treatment-related 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 (14.2)].

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 Post-marketing 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 exposure.

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, Stevens -Johnson syndrome, and

toxic epidermal necrolysis.

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% to 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 phosphate.

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/mm ).

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 to 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 post-marketing 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 the following drugs listed below have not been reported in clinical trials with

azithromycin; however, 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 or phenytoin are used with

azithromycin careful monitoring of patients is advised.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category B:

Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic

dose levels (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on body surface area, are

estimated to be 3.2 and 1.6 times, respectively, an adult daily dose of 600 mg. 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.

8.3 Nursing Mothers

Azithromycin has been reported to be excreted in breast milk in small amounts. Caution should be

exercised when azithromycin is administered to a nursing woman.

8.4 Pediatric Use

In controlled clinical studies, azithromycin has been administered to pediatric patients ranging in age

from 6 months to 12 years. For information regarding the use of azithromycin for oral suspension in the

treatment of pediatric patients, [see INDICATIONS AND USAGE (1) and DOSAGE AND

ADMINISTRATION (2)] of the prescribing information for azithromycin for oral suspension 100 mg/5

mL and 200 mg/5 mL bottles.

HIV-Infected Pediatric Patients

The safety and efficacy of azithromycin for the prevention or treatment of MAC in HIV-infected

children have not been established. Safety data are available for 72 children 5 months to 18 years of age

(mean 7 years) who received azithromycin for treatment of opportunistic infections. The mean duration

of therapy was 242 days (range 3 to 2004 days) at doses of <1 to 52 mg/kg/day (mean 12 mg/kg/day).

Adverse reactions were similar to those observed in the adult population, most of which involved the

gastrointestinal tract. Treatment-related reversible hearing impairment in children was observed in 4

subjects (5.6%). Two (2.8%) children prematurely discontinued treatment due to adverse reactions: one

due to back pain and one due to abdominal pain, hot and cold flushes, dizziness, headache, and numbness.

A third child discontinued due to a laboratory abnormality (eosinophilia). The protocols upon which

these data are based specified a daily dose of 10 to 20 mg/kg/day (oral and/or IV) of azithromycin.

8.5 Geriatric Use

In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age

(458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in

safety or effectiveness were observed between these subjects and younger subjects, and other reported

clinical experience has not identified differences in responses between the elderly and younger

patients, but greater sensitivity of some older individuals cannot be ruled out.

Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than

younger patients. [see WARNINGS AND PRECAUTIONS (5.3)].

Azithromycin 600 mg tablets contain 1.5 mg of sodium per tablet.

Geriatric Patients with Opportunistic Infections, Including (MAC) Disease

Safety data are available for 30 patients (65 to 94 years old) treated with azithromycin at doses >300

mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections,

including MAC. The adverse reactions were generally similar to that seen in younger patients, except

for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible

impairment of hearing [see DOSAGE AND ADMINISTRATION (2)].

10 OVERDOSAGE

Adverse reactions 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

Azithromycin tablets USP contains the active ingredient azithromycin, a macrolide antibacterial drug,

for oral administration. 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-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-

3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-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 C

H N O , and its molecular weight is 749.0. Azithromycin has the

following structural formula:

Azithromycin, as the monohydrate, is a white to almost white crystalline powder with a molecular

formula of C

H N O H O and a molecular weight of 767.0.

Azithromycin tablets USP contain azithromycin monohydrate equivalent to 600 mg azithromycin. They

also contain the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate,

hydroxypropyl methyl cellulose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate,

titanium dioxide and triacetin.

Organic Impurities Test Pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Azithromycin is a macrolide antibacterial drug [see MICROBIOLOGY (12.4)].

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation

techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30

after one hour of incubation. In vivo studies suggest that concentration in phagocytes may contribute to

drug distribution to inflamed tissues.

12.2 Pharmacodynamics

Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with

the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for

certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic

parameter best associated with clinical and microbiological cure has not been elucidated in clinical

trials with azithromycin.

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 oral 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

The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations

in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in

the following chart:

MEAN (CV%) PK PARAMETER

DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No.

C

(mcg/mL)

T

(hr)

C

(mcg/mL)

AUC (mcghr/mL)

T

(hr)

Urinary Excretion (% of dose)

500 mg/250 mg capsule

0.41

0.05

and 250 mg on Days 2 to 5

0.24

0.05

1200 mg/600 mg tablets

0.66

0.074

(62%)

(79%)

(49%)

(64%)

(33%)

600 mg tablet/day

0.33

0.039

(50%)

(36%)

(19%)

0.55

0.14

84.5

(18%)

(52%)

(26%)

(25%)

600 mg tablet/day (leukocytes)

10.9

4763

82.8

(49%)

(28%)

(33%)

(42%)

With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C

and C

remained essentially

unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C

levels required 5 to 7 days to reach steady state.

In asymptomatic HIV-positive adult subjects receiving 600 mg azithromycin tablets once daily for 22

days, steady state azithromycin serum levels were achieved by Day 15 of dosing.

The high values in adults 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.

Absorption

The 1 gram single-dose packet is bioequivalent to four 250 mg azithromycin capsule

When the oral suspension of azithromycin was administered with food, the C

increased by 46% and

the AUC by 14%.

The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg

tablets with food increased C

by 31% (CV=43%) while the extent of absorption (AUC) was

unchanged (mean ratio of AUCs=1; CV=55%).

Distribution

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.

The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH.

However, the extensive distribution of drug to tissues may be relevant to clinical activity.

Azithromycin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix.

Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone,

ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from

adequate and well-controlled studies of azithromycin treatment of infections in these additional body

sites, the clinical importance of these tissue concentration data is unknown.

Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum

concentration in peripheral leukocytes was 140 mcg/mL. Concentrations remained above 32 mcg/mL for

approximately 60 hours. The mean half-lives for 6 males and 6 females were 34 hours and 57 hours,

respectively. Leukocyte-to-plasma C

ratios for males and females were 258 (±77%) and 175

(±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%), respectively. The clinical

relevance of these findings is unknown.

Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-

positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (±49%).

Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/mL (±33%). The mean

leukocyte-to-serum C

ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816

(±31%). The clinical relevance of these findings is unknown.

Metabolism

In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.

Elimination

Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a

polyphasic pattern resulting in an average terminal half-life of 68 hours. Biliary excretion of

0 - last.

0-24

max

max

24

½

polyphasic pattern resulting in an average terminal half-life of 68 hours. Biliary excretion of

azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a

week, approximately 6% of the administered dose appears as unchanged drug in urine.

Specific Populations

Renal Insufficiency:

Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying

degrees of renal impairment. Following the oral administration of a single 1 g dose of azithromycin (4 x

250 mg capsules), the mean C

and AUC

increased by 5.1% and 4.2%, respectively, in subjects

with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The

mean C

and AUC

increased 61% and 35%, respectively, in subjects with end-stage renal

disease (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min).

Hepatic Insufficiency:

The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.

Gender:

There are no significant differences in the disposition of azithromycin between male and female

subjects. No dosage adjustment is recommended on the basis of gender.

Geriatric Patients:

Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger

volunteers (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to

be necessary for older patients with normal renal and hepatic function receiving treatment with this

dosage regimen [see Geriatric Use (8.5)].

Pediatric Patients:

For information regarding the pharmacokinetics of azithromycin for oral suspension in pediatric

patients, see the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200

mg/5 mL bottles.

Drug-drug Interactions:

Drug interaction studies were performed with azithromycin and other drugs likely to be co-

administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs

are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown

in Table 2.

Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of

the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-

administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the

pharmacokinetics of azithromycin. Nelfinavir significantly increased the C

and AUC of

azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs

listed in Table 2 [see DRUG INTERACTIONS (7.3)].

Table 1: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin

Co-administered Drug

Dose of Co-administered Drug

Dose of Azithromycin

n

Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic

Parameters (90% CI);

No Effect = 1

Mean C

Mean AUC

Atorvastatin

10 mg/day for 8 days

500 mg/day orally on days 6 to 8

0.83

(0.63 to 1.08)

1.01

(0.81 to 1.25)

Carbamazepine

200 mg/day for 2 days, then 200 mg

twice a day for 18 days

500 mg/day orally for days 16 to 18

0.97

(0.88 to 1.06)

0.96

(0.88 to 1.06)

Cetirizine

20 mg/day for 11 days

500 mg orally on day 7, then 250 mg/day

on days 8 to 11

1.03

(0.93 to 1.14)

1.02

(0.92 to 1.13)

Didanosine

200 mg orally twice a day for 21 days

1,200 mg/day orally on days 8 to 21

1.44

(0.85 to 2.43)

1.14

(0.83 to 1.57)

Efavirenz

400 mg/day for 7 days

600 mg orally on day 7

1.04

0.95

Fluconazole

200 mg orally single dose

1,200 mg orally single dose

1.04

(0.98 to 1.11)

1.01

(0.97 to 1.05)

Indinavir

800 mg three times a day for 5 days

1,200 mg orally on day 5

0.96

(0.86 to 1.08)

0.90

(0.81 to 1)

Midazolam

15 mg orally on day 3

500 mg/day orally for 3 days

1.27

(0.89 to 1.81)

1.26

(1.01 to 1.56)

Nelfinavir

750 mg three times a day for 11 days

1,200 mg orally on day 9

0.90

(0.81 to 1.01)

0.85

(0.78 to 0.93)

Sildenafil

100 mg on days 1 and 4

500 mg/day orally for 3 days

1.16

(0.86 to 1.57)

0.92

(0.75 to 1.12)

Theophylline

4 mg/kg IV on days 1, 11, 25

500 mg orally on day 7, 250 mg/day

on days 8 to 11

1.19

(1.02 to 1.4)

1.02

(0.86 to 1.22)

Theophylline

300 mg orally BID ×15 days

500 mg orally on day 6, then 250 mg/day

on days 7 to 10

1.09

(0.92 to 1.29)

1.08

(0.89 to 1.31)

Triazolam

0.125 mg on day 2

500 mg orally on day 1, then 250 mg/day

on day 2

1.06

1.02

Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days

1,200 mg orally on day 7

0.85

(0.75 to 0.97)/ 0.90

(0.78 to 1.03)

0.87

(0.80 to 0.95)/

0.96

(0.88 to 1.03)

Zidovudine

500 mg/day orally for 21 days

600 mg/day orally for 14 days

1.12

(0.42 to 3.02)

0.94

(0.52 to 1.7)

Zidovudine

500 mg/day orally for 21 days

1,200 mg/day orally for 14 days

1.31

(0.43 to 3.97)

(0.69 to 2.43)

Table 2: Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-

administered Drugs [see DRUG INTERACTIONS (7.3)].

Co-administered Drug

Dose of

Co-administered Drug

Dose of Azithromycin

n

Ratio (with/without

co-administered drug) of

Azithromycin Pharmacokinetic Parameters (90% CI);

No Effect = 1

Mean C

Mean AUC

Efavirenz

400 mg/day for 7 days

600 mg orally on day 7

1.22

(1.04 to 1.42)

0.92

0.82

1.07

0-120

0-120

-90% Confidence interval not reported

max

max

Fluconazole

200 mg orally single dose

1,200 mg orally single dose 18

0.82

(0.66 to 1.02)

1.07

(0.94 to 1.22)

Nelfinavir

750 mg three times a day for 11 days

1,200 mg orally on day 9

2.36

(1.77 to 3.15)

2.12

(1.80 to 2.50)

12.4 Microbiology

Azithromycin has been shown to be active against most strains of the following microorganisms, both in

vitro and in clinical infections as described in [see INDICATIONS AND USAGE (1)].

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.

Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae

Moraxella catarrhalis

Other Microorganisms

Chlamydia trachomatis

Beta-lactamase production should have no effect on azithromycin activity.

Azithromycin has been shown to be active in vitro and in the prevention and treatment of disease caused

by the following microorganisms:

Mycobacteria

Mycobacterium avium complex (MAC) consisting of:

Mycobacterium avium

Mycobacterium intracellulare

The following in vitro data are available, but their clinical significance is unknown.

Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less against

most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of

azithromycin in treating clinical infections due to these microorganisms have not been established in

adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms

Streptococci (Groups C, F, G)

Viridans group streptococci

Aerobic Gram-Negative Microorganisms

Bordetella pertussis

Campylobacter jejuni

Haemophilus ducreyi

Legionella pneumophila

Anaerobic Microorganisms

Bacteroides bivius

Clostridium perfringens

Peptostreptococcus species

Other Microorganisms

Borrelia burgdorferi

Mycoplasma pneumoniae

Treponema pallidum

Ureaplasma urealyticum

Susceptibility Testing of Bacteria Excluding Mycobacteria

The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth

medium during incubation. Incubation in a 10% CO atmosphere will result in lowering of media pH (7.2

to 6.6) within 18 hours and in an apparent reduction of the in vitro potency of azithromycin. Thus, the

initial pH of the growth medium should be 7.2 to 7.4, and the CO content of the incubation atmosphere

should be as low as practical.

Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of

95% ethanol and diluting to working concentration with water.

Dilution Techniques

Quantitative methods are used to determine minimal inhibitory concentrations that provide reproducible

estimates of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure

uses a standardized dilution method (broth, agar or microdilution) or equivalent with azithromycin

powder. The MIC values should be interpreted according to the following criteria:

MIC (mcg/mL)

Interpretation

≤ 2

Susceptible (S)

Intermediate (I)

≥ 8

Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to respond to monotherapy with

azithromycin. 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 also provides a buffer zone which prevents small uncontrolled technical

factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually

achievable drug concentrations are unlikely to be inhibitory and that other therapy should be selected.

Measurement of MIC or minimum bacterial concentration (MBC) and achieved antibacterial compound

concentrations may be appropriate to guide therapy in some infections. [see CLINICAL

PHARMACOLOGY (12)] section for further information on drug concentrations achieved in infected

-90% Confidence interval not reported

body sites and other pharmacokinetic properties of this antibacterial drug product.)

Standardized susceptibility test procedures require the use of laboratory control microorganisms.

Standard azithromycin powder should provide the following MIC values:

Microorganism

MIC (mcg/mL)

Escherichia coli ATCC 25922

2 to 8

Enterococcus faecalis ATCC 29212

1 to 4

Staphylococcus aureus ATCC 29213

0.25 to 1

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates

of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure that has

been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses

the 15 mcg azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk

test with the MIC for azithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15

mcg azithromycin disk should be interpreted according to the following criteria:

Zone Diameter (mm)

Interpretation

≥ 18

Susceptible (S)

14 to 17

Intermediate (I)

≤ 13

Resistant (R)

Interpretation should be as stated above for results using dilution techniques.

As with standardized dilution techniques, diffusion methods require the use of laboratory control

microorganisms. The 15 mcg azithromycin disk should provide the following zone diameters in these

laboratory test quality control strains:

Microorganism

Zone Diameter (mm)

Staphylococcus aureus ATCC 25923

21 to 26

In Vitro Activity of Azithromycin Against Mycobacteria

Azithromycin has demonstrated in vitro activity against MAC organisms. While gene probe techniques

may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on

MAC isolates. Azithromycin has also been shown to be active against phagocytized MAC organisms in

mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic

acid-albumin-dextrose-catalase (OADC), have been used to determine azithromycin MIC values for

MAC strains. In general, azithromycin MIC values decreased 4 to 8 fold as the pH of Middlebrook

7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with

Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same

pH. Utilization of oleic OADC in these assays has been shown to further alter MIC values. The

relationship between azithromycin and clarithromycin MIC values has not been established. In general,

azithromycin MIC values were observed to be 2 to 32 fold higher than clarithromycin independent of

the susceptibility method employed.

The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in

macrophages and tissues. [see CLINICAL PHARMACOLOGY (12)]

Drug Resistance

Complete cross-resistance between azithromycin and clarithromycin has been observed with MAC

isolates. In most isolates, a single-point mutation at a position that is homologous to the Escherichia coli

positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance

pattern.

MAC isolates exhibiting cross-resistance show an increase in azithromycin MICs to ≥128

mcg/mL with clarithromycin MICs increasing to ≥32 mcg/mL. These MIC values were determined

employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium.

The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at

this time but preclinical data suggest that reduced activity to both agents will occur after MAC strains

produce the 23S rRNA mutation.

Susceptibility Testing for MAC

The disk diffusion techniques and dilution methods for susceptibility testing against gram-positive and

gram-negative bacteria should not be used for determining azithromycin MIC values against

mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for

determining MIC values against MAC organisms have not been standardized or validated.

Azithromycin MIC values will vary depending on the susceptibility testing method employed,

composition and pH of media, and the utilization of nutritional supplements. Breakpoints to determine

whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin

have not been established.

The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial

species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been

determined.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin

has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human

lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired

fertility due to azithromycin was found in rats given daily doses up to 10 mg/kg (approximately 0.2 times

an adult daily dose of 600 mg based on body surface area).

13.2 Animal Toxicology

Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice,

rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ

systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and

rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar

to or less than the highest recommended adult human dose. This effect has been shown to be reversible

after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been

seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6

times the observed C

of 0.821 mcg/mL at the adult dose of 2 g.) Similarly, it has been shown in the

dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg/mL (1.2 times the

observed C

of 0.821 mcg/mL at the adult dose of 2 g).

Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less

than the pediatric dose of 60 mg/kg based on body surface area. It was not observed in neonatal rats

treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg/ml,

approximately 1.5 times the C

of 1.27 mcg/ml at the pediatric dose. Phospholipidosis has been

observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg/ml,

approximately 3 times the pediatric dose C

The significance of the finding for animals and for humans is unknown.

14 CLINICAL STUDIES

14.1 Clinical Studies in Patients with Advanced HIV Infection for the Prevention and Treatment of

Disease Due to Disseminated Mycobacterium Avium Complex (MAC)

[see INDICATIONS AND USAGE (1)]

Prevention of Disseminated MAC Disease

Two randomized, double-blind clinical trials were performed in patients with CD4 counts <100

cells/µL. The first trial (Study 155) compared azithromycin (1200 mg once weekly) to placebo and

enrolled 182 patients with a mean CD4 count of 35 cells/mcgL. The second trial (Study 174) 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/mcgL. The primary endpoint in these trials was disseminated

MAC disease. Other endpoints included the incidence of clinically significant MAC disease and

discontinuations from therapy for drug-related side effects.

MAC bacteremia

In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive

placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible

outcomes are in the following table:

Cumulative Incidence Rate, %: Placebo (n=89)

Month

MAC Free and Alive

MAC

Adverse Experience

Lost to Follow-up

69.7

13.5

10.1

47.2

19.1

15.7

37.1

22.5

22.5

Cumulative Incidence Rate, %: Azithromycin (n=85)

Month

MAC Free and Alive

MAC

Adverse Experience

Lost to Follow-up

84.7

63.5

16.5

11.8

44.7

11.8

25.9

17.6

The difference in the one-year cumulative incidence rates of disseminated MAC disease (placebo-

azithromycin) is 10.9%. This difference is statistically significant (p=0.037) with a 95% confidence

interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse

events and the fewer number of patients lost to follow-up on azithromycin should be taken into account

when interpreting the significance of this difference.

In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive

azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance

criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the

following table:

Cumulative Incidence Rate, %: Rifabutin (n=223)

Month

MAC Free and Alive

MAC

Adverse Experience

Lost to Follow-up

83.4

60.1

15.2

16.1

40.8

21.5

24.2

13.5

Cumulative Incidence Rate, %: Azithromycin (n=223)

Month

MAC Free and Alive

MAC

Adverse Experience

Lost to Follow-up

85.2

65.5

16.1

10.8

45.3

12.1

23.8

18.8

Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n=218)

Month

MAC Free and Alive

MAC

Adverse Experience

Lost to Follow-up

89.4

71.6

15.1

10.6

49.1

29.4

15.1

Comparing the cumulative one-year incidence rates, azithromycin monotherapy is at least as effective as

rifabutin monotherapy. The difference (rifabutin – azithromycin) in the one-year rates (7.6%) is

statistically significant (p=0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally,

azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference

(rifabutin – azithromycin/rifabutin) in the cumulative one-year incidence rates (12.5%) is statistically

significant (p<0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable

number of patients experiencing adverse events and the fewer number of patients lost to follow-up on

rifabutin should be taken into account when interpreting the significance of this difference.

In Study 174, sensitivity testing

was performed on all available MAC isolates from subjects

randomized to either azithromycin, rifabutin, or the combination. The distribution of MIC values for

azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As

the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical

relevance of these in vitro MICs as an indicator of susceptibility or resistance is not known.

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 Study 155, 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 Study 174, 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%; p=0.209).

Safety

As these patients with advanced HIV disease were taking multiple concomitant medications and

experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse reactions to

study medication. Overall, the nature of adverse reactions seen on the weekly dosage regimen of

azithromycin over a period of approximately one year in patients with advanced HIV disease were

similar to that previously reported for shorter course therapies.

INCIDENCE OF ONE OR MORE TREATMENT-RELATED ADVERSE REACTIONS IN HIV INFECTED PATIENTS RECEIVING

PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR

Includes those reactions considered possibly or probably related to study drug

>2% adverse reaction rates for any group (except uveitis)

Study 155

Study 174

Placebo (N=91)

Azithromycin 1200 mg

weekly (N=89)

Azithromycin 1200 mg

weekly (N=233)

Rifabutin 300 mg

daily (N=236)

Azithromycin + Rifabutin

(N=224)

Mean Duration of Therapy (days)

303.8

402.9

296.1

344.4

Discontinuation of Therapy

13.5

15.9

22.7

Autonomic Nervous System

Mouth Dry

Central Nervous System

Dizziness

Headache

Gastrointestinal

Diarrhea

15.4

52.8

50.2

19.1

50.9

Loose Stools

19.1

12.9

Abdominal Pain

32.2

12.3

31.7

Dyspepsia

Flatulence

10.7

Nausea

32.6

16.5

28.1

Vomiting

General

Fever

Fatigue

Malaise

Musculoskeletal

Arthralgia

Psychiatric

Anorexia

Skin & Appendages

Pruritus

Rash

11.1

Skin discoloration

Special Senses

Tinnitus

Hearing Decreased

Uveitis

Taste Perversion

Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving

azithromycin than in those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were

mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%)

of patients.

Changes in Laboratory Values

In these immunocompromised patients with advanced HIV infection, it was necessary to assess

laboratory abnormalities developing on trial with additional criteria if baseline values were outside the

relevant normal range.

PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUES

excludes subjects outside of the relevant normal range at baseline

Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin &

Rifabutin

Hemoglobin

<8 g/dL

1/51 2%

4/170 2%

4/114 4%

8/107 8%

Platelet Count<50 × 10 /mm 1/71 1%

4/260 2%

2/182 1%

6/181 3%

WBC Count

<1 × 10 /mm

0/8 0%

2/70 3%

2/47 4%

0/43 0%

Neutrophils

<500/mm

0/26 0%

4/106 4%

3/82 4%

2/78 3%

SGOT

>5 × ULN

1/41 2%

8/158 5%

3/121 3%

6/114 5%

SGPT

>5 × ULN

0/49 0%

8/166 5%

3/130 2%

5/117 4%

Alk Phos

>5 × ULN

1/80 1%

4/247 2%

2/172 1%

3/164 2%

Treatment of Disseminated MAC Disease

One randomized, double-blind clinical trial (Study 189) was performed in patients with disseminated

MAC. In this trial, 246 HIV-infected patients with disseminated MAC received either azithromycin 250

mg daily (N=65), azithromycin 600 mg daily (N=91), or clarithromycin 500 mg twice a day (N=90),

each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical

assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24.

After week 24, patients were switched to any open-label therapy at the discretion of the investigator and

followed every 3 months through the last follow-up visit of the trial. Patients were followed from the

baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during

treatment or post-treatment were obtained whenever possible.

The primary endpoint was sterilization by week 24. Sterilization was based on data from the central

laboratory, and was defined as two consecutive observed negative blood cultures for MAC,

independent of missing culture data between the two negative observations. Analyses were performed

on all randomized patients who had a positive baseline culture for MAC.

a

b

a

Upper Limit of Normal

The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a

significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day. Efficacy

results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are

described in the following table:

RESPONSE TO THERAPY OF PATIENTS TAKING ETHAMBUTOL AND

EITHER AZITHROMYCIN 600 MG DAILY OR CLARITHROMYCIN 500 MG TWICE A DAY

Azithromycin 600 mg

daily

Clarithromycin 500 mg

twice a day

95.1% CI on

difference

Patients with positive culture

at baseline

Week 24

Two consecutive negative

blood cultures

31/68 (46%)

32/57 (56%)

[-28, 7]

Mortality

16/68 (24%)

15/57 (26%)

[-18, 13]

The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24

weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day

group.

Sterilization by Baseline Colony Count

Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL

increased.

Azithromycin 600 mg (N=68)

Clarithromycin 500 mg twice a day(N=57)

groups stratified by MAC colony counts at baseline no. (%) subjects in stratified group sterile at week 24 no. (%) subjects in stratified group sterile at week 24

≤10 cfu/mL

10/15 (66.7%)

12/17 (70.6%)

11 to 100 cfu/mL

13/28 (46.4%)

13/19 (68.4%)

101 to 1,000 cfu/mL

7/19 (36.8%)

5/13 (38.5%)

1,001 to 10,000 cfu/mL

1/5 (20.0%)

1/5 (20%)

>10,000 cfu/mL

0/1 (0.0%)

1/3 (33.3%)

Susceptibility Pattern of MAC Isolates

Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of

breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was

employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged

from <4 to >256 mcg/mL and clarithromycin MICs ranged from <1 to >32 mcg/mL. The individual

MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32-fold higher

than clarithromycin MIC values.

During treatment and post-treatment follow-up for up to 3.7 years (median: 9 months) in Study 189, a

total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and

clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp

increase in MIC values. All twelve MAC isolates had azithromycin MICs ≥256 mcg/mL and

clarithromycin MICs >32 mcg/mL. These high MIC values suggest development of drug resistance.

However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have

not been established for either macrolide.

15 REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial

Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI

document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500,

Wayne, Pennsylvania 19087, USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk

Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11,

Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania

19087, USA, 2012.

3. Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium

chemoprophylaxis. Am J Med 1997; 102(5C):37-49.

4. Meier A, Kirshner P, Springer B, et al. Identification of mutations in 23S rRNA gene of

clarithromycin-resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994; 38:381-

384.

5. Methodology per Inderlied CB, et al. Determination of In Vitro Susceptibility of Mycobacterium

avium Complex Isolates to Antimicrobial Agents by Various Methods. Antimicrob Agents

Chemother. 1987; 31:1697-1702.

16 HOW SUPPLIED/STORAGE AND HANDLING

Azithromycin Tablets USP, 600 mg are supplied as white, oval shaped film-coated tablets, engraved

with "LU" on one side and "L13" on the other side containing azithromycin monohydrate USP equivalent

to 600 mg of azithromycin USP.

These are packaged in bottles of 30 tablets as follows:

Bottles of 30 Tablets: NDC 68180-162-06

Tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP

Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Azithromycin tablets may be taken with or without food. However, increased tolerability has been

observed when tablets are taken with food.

Patients should also be cautioned not to take aluminum-and magnesium-containing antacids and

azithromycin simultaneously.

The patient should be directed to discontinue azithromycin immediately and contact a physician if any

signs of an allergic reaction occur.

Patients should be counseled that antibacterial drugs, including azithromycin, should only be used to

treat bacterial infections. They do not treat viral infections (e.g., the common cold). When azithromycin

is prescribed to treat bacterial infection, patients should be told that although it is common to feel better

early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not

completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and

(2) increase the likelihood that bacteria will develop resistance and will not be treatable by azithromycin

[95% confidence interval] on difference in rates (azithromycin-clarithromycin)

Primary endpoint

*

or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibacterial which usually ends when the antibiotic is

discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and

bloody stools (with or without stomach cramps and fever) even as late as two or more months after

having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as

soon as possible.

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, Maryland 21202

United States

Manufactured by:

Lupin Limited

Goa - 403722

India

May 2015 ID #214409

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Azithromycin Tablets USP, 600 mg

30 Tablets- Container Label

NDC 68180-162-06

AZITHROMYCIN MONOHYDRATE

azithromycin monohydrate tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:5729 7-16 2

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

AZITHRO MYCIN MO NO HYDRATE (UNII: JTE4MNN1MD) (AZITHROMYCIN ANHYDROUS -

UNII:J2KLZ20 U1M)

AZITHROMYCIN

ANHYDROUS

6 0 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CALCIUM PHO SPHATE, DIBASIC, ANHYDRO US (UNII: L11K75P9 2J)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

HYPRO MELLO SE 2 9 10 ( 15 MPA.S) (UNII: 36 SFW2JZ0 W)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

LU;L13

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:5729 7-16 2-0 6

30 in 1 CONTAINER; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 6 540 0

0 7/22/20 15

Labeler -

LUPIN LIMIT ED (675923163)

Registrant -

LUPIN LIMIT ED (675923163)

LUPIN LIMITED

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

LUPIN LIMITED

6 776 0 0 414

manufacture(5729 7-16 2) , pack(5729 7-16 2)

Revised: 2/2016

Similar products

Search alerts related to this product

Share this information