1.1 Acute Bacterial Sinusitis in Adults and Community-Acquired Pneumonia

Zmax (azithromycin) is a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. [See Clinical Studies (14)]

Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Community-acquired pneumonia in adults and pediatric patients six months of age or older due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based on extrapolation of adult efficacy. [See Use in Specific Populations (8.4)]

1.2 Limitations of Use

Zmax is not recommended for use in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:

• patients with cystic fibrosis,
• patients with nosocomial infections,
• patients with known or suspected bacteremia,
• patients requiring hospitalization,
• elderly or debilitated patients, or
• patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).

1.3 Usage

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

2.1 Adults

Zmax should be taken as a single 2 g dose. Zmax provides a full course of antibacterial therapy in a single oral dose. It is recommended that Zmax be taken on an empty stomach (at least 1 hr before or 2 hr following a meal).

2.2 Pediatric Patients

For pediatric patients 6 months and older, Zmax should be taken as a single dose of 60 mg/kg body weight for patients weighing less than 34 kg. It is recommended that Zmax be taken on an empty stomach (at least 1 hr before or 2 hrs following a meal).

Pediatric patients weighing 34 kg should receive the adult dose (2 g).

2.3 Additional Treatment after Vomiting with Zmax

In the event that a patient vomits within 5 minutes of administration, the health care provider should consider additional antibiotic treatment since there would be minimal absorption of azithromycin. Since insufficient data exist on absorption of azithromycin if a patient vomits between 5 and 60 minutes following administration, alternative therapy should be considered. Neither a second dose of Zmax nor alternative treatment is warranted if vomiting occurs ≥60 minutes following administration, in patients with normal gastric emptying. In patients with delayed gastric emptying, alternative therapy should be considered.

2.4 Instructions for the Pharmacist

Constitute with 60 mL of water and replace cap. Shake bottle well before dispensing. Do not refrigerate. Constituted suspension should be consumed within 12 hr.

For pediatric dosing in patients weighing less than 34 kg, use of a dosing device is recommended. The pharmacist should inform the patient's caregiver that any suspension remaining after dosing MUST be discarded.

4.1 Hypersensitivity Reactions

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

4.2 Cholestatic Jaundice/Hepatic Dysfunction

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

5.1 Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis, Acute Generalized Exanthematous Pustulosis (AGEP), Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy using other formulations. Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined.

If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

5.2 Hepatotoxicity

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

5.3 Infantile Hypertrophic Pyloric Stenosis (IHPS)

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

5.4 QT Prolongation

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

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

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

5.5 Cardiovascular Death

Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular mortality observed in these studies ranged from 20 to 400 per million azithromycin treatment courses. This potential risk was noted to be greater during the first five days of azithromycin use and does not appear to be limited to those patients with preexisting cardiovascular diseases. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. Consider balancing this potential risk with treatment benefits when prescribing Zmax.

5.6 Clostridioides difficile-Associated Diarrhea (CDAD)

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

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

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

5.7 Exacerbation of Myasthenia Gravis

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

5.8 Gastrointestinal Disturbances

A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax was administered to a limited number of subjects with GFR<10 mL/min. [See Use in Specific Populations (8.6)]

5.9 Development of Drug Resistant Bacteria

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

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.

6.2 Postmarketing Experience with Other Azithromycin Products

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: Palpitations and arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation, torsades de pointes, and cardiovascular death.
Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration.
General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis.
Genitourinary: Interstitial nephritis, acute renal failure and vaginitis.
Hematopoietic: Thrombocytopenia, mild neutropenia.
Liver/biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin. [See Warnings and Precautions (5.2)].
Nervous system: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope.
Psychiatric: Aggressive reaction and anxiety.
Skin/appendages: Pruritus, rash, photosensitivity, serious skin reactions including erythema multiforme, AGEP, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS.
Special senses: Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss.

6.3 Laboratory Abnormalities

In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials in adults and pediatric patients:

7.1 Nelfinavir

Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see Adverse Reactions (6)]

7.2 Warfarin

Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.

7.3 Potential Drug-Drug Interaction with Macrolides

Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been established.

8.5 Geriatric Use

Data collected from the azithromycin capsule and tablet formulations indicate that a dosage adjustment does not appear to be necessary for older patients with normal renal function (for their age) and hepatic function receiving treatment with Zmax.

In clinical trials of Zmax, 17% of subjects were at least 65 years of age (214/1292) and 5% of subjects (59/1292) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Elderly patients may be more susceptible to development of torsades de pointes arrhythmia than younger patients. [See Warnings and Precautions (5.4)]

8.6 Renal Impairment

No dosage adjustment is recommended for patients GFR >10 mL/min. Caution should be exercised when Zmax is administered to patients with GFR <10 mL/min, due to a higher incidence of gastrointestinal adverse events (8 of 19 subjects) observed in a limited number of subjects with GFR <10 mL/min. [See Clinical Pharmacology (12)]

8.7 Gender

The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax. However, previous studies have demonstrated no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment of Zmax is recommended based on gender.

12.1 Mechanism of Action

Azithromycin is a macrolide antibacterial drug. [See Clinical Pharmacology (12.4)]

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Zmax is an extended-release microsphere formulation. Based on data obtained from studies evaluating the pharmacokinetics of azithromycin in healthy adult subjects a higher peak serum concentration (Cmax) and greater systemic exposure (AUC 0–24) of azithromycin are achieved on the day of dosing following a single 2 g dose of Zmax versus 1.5 g of azithromycin tablets administered over 3 days (500 mg/day) or 5 days (500 mg on day 1, 250 mg/day on days 2–5) [Table 2]. Consequently, due to these different pharmacokinetic profiles, Zmax is not interchangeable with azithromycin tablet 3-day and 5-day dosing regimens.

12.4 Microbiology

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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.1 to 0.2 times the adult human oral dose of 2 g based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain.

13.2 Animal Toxicology and/or Pharmacology

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 treated with azithromycin at doses which, expressed on the basis of body surface area, are approximately one-sixth the recommended adult human dose, and in rats treated at doses approximately one-fourth the 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 Cmax 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 Cmax 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 the 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 Cmax 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 Cmax.

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

14.1 Acute Bacterial Maxillary Sinusitis

Adult subjects with a diagnosis of acute bacterial maxillary sinusitis were evaluated in a randomized, double-blind, multicenter study; a maxillary sinus tap was performed on all subjects at baseline. Clinical evaluations were conducted for all subjects at the TOC visit, 7 to 14 days post-treatment. Two hundred seventy (270) subjects were treated with a single 2 g oral dose of Zmax and 268 subjects were treated with levofloxacin, 500 mg orally once daily for 10 days. A subject was considered a cure if signs and symptoms related to the acute infection had resolved, or if clinical improvement was such that no additional antibiotics were deemed necessary. The clinical response for the primary population, Clinical Per Protocol Subjects, is presented below.

Clinical response by pathogen in the Bacteriologic Per Protocol population is presented below.

14.2 Community-Acquired Pneumonia

Adult subjects with a diagnosis of mild-to-moderate community-acquired pneumonia were evaluated in two, randomized, double-blind, multicenter studies. In both studies, clinical and microbiologic evaluations were conducted for all subjects at the Test of Cure (TOC) visit, 7 to 14 days post-treatment. In Trial 1, 247 subjects were treated with a single 2 g oral dose of Zmax and 252 subjects were treated with clarithromycin extended-release, 1 g orally once daily for 7 days. In Trial 2, 211 subjects were treated with a single 2.0 g oral dose of Zmax and 212 subjects were treated with levofloxacin, 500 mg orally once daily for 7 days. A patient was considered a cure if signs and symptoms related to the acute infection had resolved, or if clinical improvement was such that no additional antibiotics were deemed necessary; in addition, the chest x-ray performed at the TOC visit was to be either improved or stable. The clinical response at TOC for the primary population, Clinical Per Protocol Subjects, is presented in the table below.

Clinical response by pathogen in the Bacteriologic Per Protocol population, across both studies, is presented below:

Storage

Before constitution, store dry powder at or below 30°C (86°F).

After constitution, store suspension at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.

Constituted suspension should be consumed within 12 hr. For adult patients, the entire bottle should be consumed. For pediatric patients, any suspension remaining after dosing MUST be discarded.

General Patient Counseling

• Patients should be instructed to take Zmax on an empty stomach (at least 1 hr before or 2 hr following a meal).
• To ensure accurate dosing for children, use of a dosing spoon, medicine syringe, or cup is recommended.
• Patients should be told that Zmax needs time to work, so the patient may not feel better right away. If the patient's symptoms do not improve in a few days, the patient or their guardian should call their healthcare provider.
• Patients should be instructed to immediately contact a physician if any signs of an allergic reaction occur.
• Direct parents or caregivers to contact their physician if vomiting and irritability with feeding occurs in the infant.
• Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.
• Patients who vomit within the first hr should contact their health care provider about further treatment.
• Keep bottle tightly closed. Store at room temperature. Use within 12 hr of constitution. Shake bottle well before use. Adult patients should consume the entire contents of the bottle; pediatric patients should take the recommended dose and MUST discard any unused portion.
• Patients should be advised that Zmax may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide.

Patients should be counseled that antibacterial drugs including Zmax should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Not taking the complete prescribed dose 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 Zmax or other antibacterial drugs in the future.