azithromycin monohydrate (azithromycin monohydrate 600 mg) Dailymed

Generic: azithromycin monohydrate is used for the treatment of Chlamydia Infections Endocarditis, Bacterial Haemophilus Infections Hypersensitivity Liver Diseases Mycobacterium Infections, Nontuberculous Otitis Media Pneumonia, Mycoplasma Skin Diseases, Infectious Staphylococcal Infections Streptococcal Infections Tonsillitis Urethritis Neisseriaceae Infections

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1 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.

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 uled 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

Mycobacterial Infections (2.2)

[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

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

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)

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

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)

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:

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

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

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/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 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

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)

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 uled 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

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)

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 C₃₈H₇₂N₂O₁₂, 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 C₃₈H₇₂N₂O₁₂•H₂O 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_m _a _x ( mcg / mL ) T_m _a _x ( hr ) C₂ ₄ ( mcg / mL ) AUC ( mcg•hr / mL ) T _½ ( hr ) Urinary Excretion (% of dose )

500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6AUC₀ _- ₂ ₄; ^b0-last. – 4.5

and 250 mg on Days 2 to 5 12 5 0.24 3.2 0.05 2.1 – 6.5

1200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8^b 40 –

%CV (62%) (79%) (49%) (64%) (33%)

600 mg tablet/day 7 1 0.33 2 0.039 2.4

%CV 25% (50%) (36%) (19%)

7 22 0.55 2.1 0.14 5.8 84.5 -

%CV (18%) (52%) (26%) (25%) -

600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763 82.8 -

%CV (49%) (28%) (33%) (42%) - -

With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C_min and C_max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C_min levels required 5 to 7 days to reach steady state.

In 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_max 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_max 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_max 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_max 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 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_maxand AUC_0-120 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_max and AUC_0-120 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 uled in Table 1. No dosage adjustment of drugs uled 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_max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs uled 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_m _a _x Mean AUC

Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6 to 8 12 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 7 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 14 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 6 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 14 1.04-90% Confidence interval not reported 0.95

Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 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 18 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 12 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 14 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 12 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 10 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 8 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 12 1.06 1.02

Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 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 5 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 4 1.31(0.43 to 3.97) 1.3(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_m _a _x Mean AUC

Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92-90% Confidence interval not reported

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 14 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% CO₂atmosphere 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 CO₂ 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 method¹(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)

4 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 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 procedure² 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.^3,4 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_max 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_max 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_max 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_max.

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

6 69.7 13.5 6.7 10.1

12 47.2 19.1 15.7 18

18 37.1 22.5 18 22.5

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

Month MAC Free and Alive MAC Adverse Experience Lost to Follow - up

6 84.7 3.5 9.4 2.4

12 63.5 8.2 16.5 11.8

18 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

6 83.4 7.2 8.1 1.3

12 60.1 15.2 16.1 8.5

18 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

6 85.2 3.6 5.8 5.4

12 65.5 7.6 16.1 10.8

18 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

6 89.4 1.8 5.5 3.2

12 71.6 2.8 15.1 10.6

18 49.1 6.4 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 testing⁵was 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^a ^{ADVERSE REACTIONS^b
^{IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR}}
^a ^{Includes those reactions considered possibly or probably related to study drug}

^b ^{>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) 303.8 402.9 315 296.1 344.4

Discontinuation of Therapy 2.3 8.2 13.5 15.9 22.7

Autonomic Nervous System

Mouth Dry 0 0 0 3 2.7

Central Nervous System

Dizziness 0 1.1 3.9 1.7 0.4

Headache 0 0 3 5.5 4.5

Gastrointestinal

Diarrhea 15.4 52.8 50.2 19.1 50.9

Loose Stools 6.6 19.1 12.9 3 9.4

Abdominal Pain 6.6 27 32.2 12.3 31.7

Dyspepsia 1.1 9 4.7 1.7 1.8

Flatulence 4.4 9 10.7 5.1 5.8

Nausea 11 32.6 27 16.5 28.1

Vomiting 1.1 6.7 9 3.8 5.8

General

Fever 1.1 0 2.1 4.2 4.9

Fatigue 0 2.2 3.9 2.1 3.1

Malaise 0 1.1 0.4 0 2.2

Musculoskeletal

Arthralgia 0 0 3 4.2 7.1

Psychiatric

Anorexia 1.1 0 2.1 2.1 3.1

Skin & Appendages

Pruritus 3.3 0 3.9 3.4 7.6

Rash 3.2 3.4 8.1 9.4 11.1

Skin discoloration 0 0 0 2.1 2.2

Special Senses

Tinnitus 4.4 3.4 0.9 1.3 0.9

Hearing Decreased 2.2 1.1 0.9 0.4 0

Uveitis 0 0 0.4 1.3 1.8

Taste Perversion 0 0 1.3 2.5 1.3

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^a
^aexcludes 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 × 10³/mm³ 1/71   1% 4/260   2% 2/182    1% 6/181   3%

WBC Count <1 × 10³/mm³ 0/8     0% 2/70   3% 2/47      4% 0/43   0%

Neutrophils <500/mm³ 0/26   0% 4/106   4% 3/82      4% 2/78   3%

SGOT >5 × ULNUpper Limit of Normal 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.

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% confidence interval] on difference in rates (azithromycin-clarithromycin)95 . 1 % CI on difference

Patients with positive culture at baseline 68 57

Week 24

Two consecutive negative blood culturesPrimary endpoint 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

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.

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.

Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium chemoprophylaxis. Am J Med 1997; 102(5C):37-49.

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.

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 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

MEAN (CV%) PK PARAMETER
DOSE / DOSAGE FORM ( serum , except as indicated )	Subjects	Day No .	C_m _a _x ( mcg / mL )	T_m _a _x ( hr )	C₂ ₄ ( mcg / mL )	AUC ( mcg•hr / mL )	T _½ ( hr )	Urinary Excretion (% of dose )
500 mg/250 mg capsule	12	1	0.41	2.5	0.05	2.6AUC₀ _- ₂ ₄; ^b0-last.	–	4.5
and 250 mg on Days 2 to 5	12	5	0.24	3.2	0.05	2.1	–	6.5
1200 mg/600 mg tablets	12	1	0.66	2.5	0.074	6.8^b	40	–
%CV			(62%)	(79%)	(49%)	(64%)	(33%)
600 mg tablet/day	7	1	0.33	2	0.039	2.4
%CV			25%	(50%)	(36%)	(19%)
	7	22	0.55	2.1	0.14	5.8	84.5	-
%CV			(18%)	(52%)	(26%)	(25%)		-
600 mg tablet/day (leukocytes)	7	22	252	10.9	146	4763	82.8	-
%CV			(49%)	(28%)	(33%)	(42%)	-	-

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_m _a _x	Mean AUC
Atorvastatin	10 mg/day for 8 days	500 mg/day orally on days 6 to 8	12	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	7	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	14	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	6	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	14	1.04-90% Confidence interval not reported	0.95
Fluconazole	200 mg orally single dose	1,200 mg orally single dose	18	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	18	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	12	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	14	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	12	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	10	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	8	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	12	1.06	1.02
Trimethoprim/ Sulfamethoxazole	160 mg/800 mg/day orally for 7 days	1,200 mg orally on day 7	12	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	5	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	4	1.31(0.43 to 3.97)	1.3(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_m _a _x	Mean AUC
Efavirenz	400 mg/day for 7 days	600 mg orally on day 7	14	1.22 (1.04 to 1.42)	0.92-90% Confidence interval not reported
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	14	2.36 (1.77 to 3.15)	2.12 (1.80 to 2.50)

INCIDENCE OF ONE OR MORE TREATMENT-RELATED^a ^{ADVERSE REACTIONS^b
^{IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR}}
^a ^{Includes those reactions considered possibly or probably related to study drug}
^b ^{>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	315	296.1	344.4
Discontinuation of Therapy	2.3	8.2	13.5	15.9	22.7
Autonomic Nervous System
Mouth Dry	0	0	0	3	2.7
Central Nervous System
Dizziness	0	1.1	3.9	1.7	0.4
Headache	0	0	3	5.5	4.5
Gastrointestinal
Diarrhea	15.4	52.8	50.2	19.1	50.9
Loose Stools	6.6	19.1	12.9	3	9.4
Abdominal Pain	6.6	27	32.2	12.3	31.7
Dyspepsia	1.1	9	4.7	1.7	1.8
Flatulence	4.4	9	10.7	5.1	5.8
Nausea	11	32.6	27	16.5	28.1
Vomiting	1.1	6.7	9	3.8	5.8
General
Fever	1.1	0	2.1	4.2	4.9
Fatigue	0	2.2	3.9	2.1	3.1
Malaise	0	1.1	0.4	0	2.2
Musculoskeletal
Arthralgia	0	0	3	4.2	7.1
Psychiatric
Anorexia	1.1	0	2.1	2.1	3.1
Skin & Appendages
Pruritus	3.3	0	3.9	3.4	7.6
Rash	3.2	3.4	8.1	9.4	11.1
Skin discoloration	0	0	0	2.1	2.2
Special Senses
Tinnitus	4.4	3.4	0.9	1.3	0.9
Hearing Decreased	2.2	1.1	0.9	0.4	0
Uveitis	0	0	0.4	1.3	1.8
Taste Perversion	0	0	1.3	2.5	1.3

PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUES^a
^aexcludes 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 × 10³/mm³	1/71 1%	4/260 2%	2/182 1%	6/181 3%
WBC Count	<1 × 10³/mm³	0/8 0%	2/70 3%	2/47 4%	0/43 0%
Neutrophils	<500/mm³	0/26 0%	4/106 4%	3/82 4%	2/78 3%
SGOT	>5 × ULNUpper Limit of Normal	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%

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"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

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MIC ( mcg / mL )	Interpretation
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

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

Zone Diameter ( mm )	Interpretation
≥ 18	Susceptible (S)
14 to 17	Intermediate (I)
≤ 13	Resistant (R)

Microorganism	Zone Diameter ( mm )
Staphylococcus aureus ATCC 25923	21 to 26

Cumulative Incidence Rate , %: Placebo ( n = 89 )
Month	MAC Free and Alive	MAC	Adverse Experience	Lost to Follow - up
6	69.7	13.5	6.7	10.1
12	47.2	19.1	15.7	18
18	37.1	22.5	18	22.5
Cumulative Incidence Rate , %: Azithromycin ( n = 85 )
Month	MAC Free and Alive	MAC	Adverse Experience	Lost to Follow - up
6	84.7	3.5	9.4	2.4
12	63.5	8.2	16.5	11.8
18	44.7	11.8	25.9	17.6

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% confidence interval] on difference in rates (azithromycin-clarithromycin)95 . 1 % CI on difference
Patients with positive culture at baseline	68	57
Week 24
Two consecutive negative blood culturesPrimary endpoint	31/68 (46%)	32/57 (56%)	[-28, 7]
Mortality	16/68 (24%)	15/57 (26%)	[-18, 13]

	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%)

azithromycin monohydrate (azithromycin monohydrate 600 mg) Dailymed

Drug Classes

Version History

FDA Adverse Reactions

Recent Major Changes

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

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