Azithromycin: Package Insert and Label Information

AZITHROMYCIN- azithromycin dihydrate tablet, film coated
AvKARE

1 INDICATIONS AND USAGE

Azithromycin tablets are 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, taken alone or in combination with rifabutin at its approved dose, are 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, taken in combination with ethambutol, are indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection [see Use in Specific Populations ( 8.4) and Clinical Studies ( 14.1)].

1.3 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin tablets should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION

[see Indications and Usage ( 1)]

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

For pediatric suspension see the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles.

2.2 Mycobacterial Infections

Prevention of Disseminated MAC Infections

The recommended dose of azithromycin tablets for the prevention of disseminated Mycobacterium avium complex (MAC) disease is: 1,200 mg taken once weekly. This dose of azithromycin tablets may be combined with the approved dosage regimen of rifabutin.

Treatment of Disseminated MAC Infections

Azithromycin tablets 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, oblong, biconvex, film-coated tablets, debossed with “600” on one side, containing azithromycin dihydrate, USP equivalent to 600 mg azithromycin. These are packaged in bottles of 30 tablets.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug.

4.2 Hepatic Dysfunction

Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis, have been reported rarely in patients on azithromycin therapy. [see Contraindications ( 4.1)]

Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is presently unknown.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that allergic symptoms may reappear when symptomatic therapy is discontinued.

5.2 Hepatotoxicity

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.

5.3 Infantile Hypertrophic Pyloric Stenosis (IHPS)

Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs.

5.4 QT Prolongation

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including:

• patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure
• patients on drugs known to prolong the QT interval
• patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval.

5.5 Clostridium difficile -Associated Diarrhea (CDAD)

CDAD has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin – producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.6 Exacerbation of Myasthenia Gravis

Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.

5.8 Development of Drug-Resistant Bacteria

Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, most of the reported adverse reactions were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued azithromycin therapy because of 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 ( 14.1)]

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 1,200 mg weekly regimen

The nature of adverse reactions seen with the 1,200 mg weekly dosing regimen for the prevention of Mycobacterium avium infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens. [see Clinical Studies ( 14)]

Chronic therapy with 600 mg daily regimen combined with ethambutol

The nature of adverse reactions seen with the 600 mg daily dosing regimen for the treatment of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short term dosing regimens. Five percent of patients experienced reversible hearing impairment in the pivotal clinical trial for the treatment of disseminated MAC in patients with AIDS. Hearing impairment has been reported with macrolide antibiotics, especially at higher doses. Other treatment-related adverse reactions occurring in > 5% of subjects and seen at any time during a median of 87.5 days of therapy include: abdominal pain (14%), nausea (14%), vomiting (13%), diarrhea (12%), flatulence (5%), headache (5%), and abnormal vision (5%). Discontinuations from treatment due to laboratory abnormalities or adverse reactions considered related to study drug occurred in 8 of 88 (9.1%) of subjects.

Single 1 gram dose regimen

Overall, the most common adverse reactions in patients receiving a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen.

Adverse reactions that occurred in patients on the single 1 gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug 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, AGEP, Stevens-Johnson Syndrome, toxic epidermal necrolysis, and DRESS.

Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, and reports of taste/smell perversion and/or loss.

6.3 Laboratory Abnormalities

Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials
were reported as follows:

• With an incidence of 1 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 3,000 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 ³).

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.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.