azithromycin
Dosage Form: powder, for oral suspension
FULL PRESCRIBING INFORMATION
Indications and Usage for Zmax
Zmax is indicated for the treatment with mild to moderate infections caused by susceptible isolates 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)]
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and other antibacterial drugs, Zmax 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.
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to Zmax. [See Clinical Pharmacology (12.4)] Therapy with Zmax may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.
Zmax Dosage and Administration
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 hour before or 2 hours following a meal).
Pediatric patients
For pediatric patients 6 months and older, Zmax should be taken as a single dose of 60 mg/kg (equivalent to 27 mg/lb) body weight. The Zmax dose in mL is equivalent to the child's weight in lb (1 mL/lb dose, see Table 1 below), for a body weight of less than 75 lb (34 kg). It is recommended that Zmax be taken on an empty stomach (at least 1 hour before or 2 hours following a meal).
Pediatric patients weighing 75 lb (34 kg) or more should receive the adult dose (2 g).
| Dosing Calculated on 1 mL/lb, Dose 1 mL of Suspension for every 1 lb of Body Weight for Children <75 lb (34 kg)* | |||
|---|---|---|---|
| Weight | 1 mL/lb Dose | ||
| Lb | Kg | Dose | Volume |
| (mg) | (mL) | ||
| |||
| 10 | 5 | 270 | 10 |
| 15 | 7 | 405 | 15 |
| 20 | 9 | 540 | 20 |
| 25 | 11 | 675 | 25 |
| 30 | 14 | 810 | 30 |
| 35 | 16 | 945 | 35 |
| 40 | 18 | 1080 | 40 |
| 45 | 20 | 1215 | 45 |
| 50 | 23 | 1350 | 50 |
| 55 | 25 | 1485 | 55 |
| 60 | 27 | 1620 | 60 |
| 65 | 30 | 1755 | 65 |
| 70 | 32 | 1890 | 70 |
| ≥75 | 34 | 2000 | Consume entire contents of bottle |
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.
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 hours.
For pediatric dosing in patients weighing less than 75 lb (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.
Dosage Forms and Strengths
Each bottle of Zmax contains azithromycin dihydrate equivalent to 2 g of azithromycin. After constitution with 60 mL of water, each mL of suspension contains 27 mg of azithromycin. The suspension is a white or off-white color and has a cherry/banana flavor.
Contraindications
Hypersensitivity reactions
Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide antibiotic.
Cholestatic jaundice/hepatic dysfunction
Zmax is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
Warnings and Precautions
Allergic and skin reactions
Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other formulations. Although rare, 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 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.
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.
Clostridium difficile-associated diarrhea
Clostridium 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.
Exacerbation of myasthenia gravis
Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
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)]
Prolongation of the QT interval
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization.
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.
Adverse Reactions
Clinical studies 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.
Adults:
The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single 2 g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial sinusitis.
In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions were gastrointestinal in nature and mild to moderate in severity.
Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2 g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for Zmax and 10% for pooled comparators.
Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of <1% included the following:
Cardiovascular: palpitations, chest pain
Gastrointestinal: constipation, dyspepsia, flatulence, gastritis, oral moniliasis
Genitourinary: vaginitis
Nervous System: dizziness, vertigo
General: asthenia
Allergic: rash, pruritus, urticaria
Special Senses: taste perversion
Laboratory Abnormalities
In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials:
- -
- with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate;
- -
- with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN, creatinine, alterations in potassium.
Where follow-up was provided, changes in laboratory tests appeared to be reversible.
Pediatric Patients:
The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3 months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax.
As in adults, the most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27 mg/lb) of Zmax.
In a study with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%) loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an incidence greater than 1% began on the day of dosing in these subjects [43% (68/160)] and most [53% (84/160)] resolved within 48 hours of onset. Treatment-related adverse events that were not gastrointestinal, occurring with a frequency ≥ 1% were: rash (5%), anorexia (2%), fever (2%), and dermatitis (2%).
In a second study of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%), nausea (4%) and abdominal pain (4%).
A third study investigated the tolerability of two different concentrations of azithromycin oral suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin. The study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different from the vomiting for the more concentrated suspension Across both treatment arms, the only treatment-related adverse events with a frequency of ≥ 1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120).
Treatment-related adverse reactions with a frequency of < 1% following Zmax treatment in all 907 pediatric subjects in the Phase 3 studies were:
Body as a whole: chills, fever, flu syndrome, headache;
Digestive: abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder, hepatitis;
Hemic and Lymphatic: leukopenia;
Nervous System: agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability, parasthesia, somnolence;
Respiratory: asthma, bronchitis, cough increased, dyspnea, pharyngitis, rhinitis;
Skin and Appendages: dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria;
Special Senses: otitis media, taste perversion;
Urogenital: dysuria.
Laboratory Abnormalities
In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax pediatric clinical trials:
- -
- with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium; decreased lymphocytes; and alterations in neutrophils;
- -
- with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and alterations in sodium and glucose.
Postmarketing experience with other azithromycin products
Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.
Adverse events reported with azithromycin immediate release formulations during the postmarketing period 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 rare reports of QT prolongation and torsades de pointes.
Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration
General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal)
Genitourinary: interstitial nephritis, acute renal failure, moniliasis 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, rarely 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 rare reports of taste/smell perversion and/or loss
Drug Interactions
Warfarin
Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on mg/m2, are estimated to be approximately equivalent to one or one-half of, respectively, the single adult oral dose of 2 g. 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.
Nursing Mothers
It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been established.
Community-Acquired Pneumonia: The safety and effectiveness of Zmax have been established in pediatric patients 6 months of age or older with community-acquired pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. Use of Zmax for these patients is supported by evidence from adequate and well-controlled studies of Zmax in adults with additional safety and pharmacokinetic data in pediatric patients. [See DOSAGE AND ADMINISTRATION (2.2), ADVERSE REACTIONS (6), CLINICAL PHARMACOLOGY (12.3)]
Acute bacterial sinusitis: Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis have not been established.
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.
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)]
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.
Overdosage
Adverse events 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.
Zmax Description
Zmax (azithromycin extended release) for oral suspension contains the active ingredient azithromycin (as azithromycin dihydrate), an azalide, a subclass of macrolide antibiotics. 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 dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12•2H2O and a molecular weight of 785.0.
Zmax is a single-dose, extended release formulation of microspheres for oral suspension containing azithromycin (as azithromycin dihydrate) and the following excipients: glyceryl behenate, poloxamer 407, sucrose, sodium phosphate tribasic anhydrous, magnesium hydroxide, hydroxypropyl cellulose, xanthan gum, colloidal silicon dioxide, titanium dioxide, artificial cherry flavor, and artificial banana flavor.
Note: Each bottle of Zmax 2 g for oral suspension contains approximately 148 mg of sodium and 19 g of sucrose. Constituted Zmax oral suspension contains approximately 2 mg/mL of sodium and 0.26 g/mL of sucrose.
Zmax - Clinical Pharmacology
Mechanism of Action
Azithromycin is an antimicrobial agent [See Clinical Pharmacology (12.4)]
Pharmacodynamics
Based on animal models of infection, the antimicrobial 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 Zmax.
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.
| Pharmacokinetic Parameter* | Azithromycin Regimen | ||
|---|---|---|---|
| Zmax [N=41]† | 3-day ‡ [N=12] | 5-day ‡ [N=12] | |
| SD = standard deviation Cmax = maximum serum concentration Tmax = time to Cmax AUC = area under concentration vs. time curve t1/2 = terminal serum half-life | |||
| |||
| Cmax (µg/mL) | 0.821 (0.281) | 0.441 (0.223) | 0.434 (0.202) |
| Tmax§ (hr) | 5.0 (2.0–8.0) | 2.5 (1.0–4.0) | 2.5 (1.0–6.0) |
| AUC0–24 (µg∙hr/mL) | 8.62 (2.34) | 2.58 (0.84) | 2.60 (0.71) |
| AUC0–∞¶ (µg∙hr/mL) | 20.0 (6.66) | 17.4 (6.2) | 14.9 (3.1) |
| t1/2 (hr) | 58.8 (6.91) | 71.8 (14.7) | 68.9 (13.8) |
Absorption
The bioavailability of Zmax relative to azithromycin immediate release (IR) (powder for oral suspension) was 83%. On average, peak serum concentrations were achieved approximately 2.5 hours later following Zmax administration and were lower by 57%, compared to 2 g azithromycin IR. Thus, single 2 g doses of Zmax and azithromycin IR are not bioequivalent and are not interchangeable.
Effect of food on absorption: A high-fat meal increased the rate and extent of absorption of a 2 g dose of Zmax (115% increase in Cmax, and 23% increase in AUC0–72) compared to the fasted state. A standard meal also increased the rate of absorption (119% increase in Cmax) and with less effect on the extent of absorption (12% increase in AUC0–72) compared to administration of a 2 g Zmax dose in the fasted state.
Effect of antacids: Following the administration of Zmax with an aluminum and magnesium hydroxide antacid, the rate and extent of azithromycin absorption were not altered.
Distribution
The serum protein binding of azithromycin is concentration dependent, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg.
Azithromycin concentrates in fibroblasts, epithelial cells, macrophages, and circulating neutrophils and monocytes. Higher azithromycin concentrations in tissues than in plasma or serum have been observed. White blood cell and lung exposure data in humans following a single 2 g dose of Zmax in adults are shown in Table 3. Following a 2 g single dose of Zmax, azithromycin achieved higher exposure (AUC0–120) in mononuclear leukocytes (MNL) and polymorphonuclear leukocytes (PMNL) than in serum. The azithromycin exposure (AUC0–72) in lung tissue and alveolar cells (AC) was approximately 100 times that in serum; and the exposure in epithelial lining fluid (ELF) was also higher (approximately 2–3 times) than in serum. The clinical significance of this distribution data is unknown.
| A single 2 g dose of Zmax | ||||
|---|---|---|---|---|
| Abbreviation: WBC: white blood cells; MNL: mononuclear leukocytes; PMNL: polymorphonuclear leukocytes; ELF: Epithelial lining fluid | ||||
| ||||
| WBC | Cmax (µg/mL) | AUC0–24 (µg∙hr/mL) | AUC0–120 (µg∙hr/mL) | Ct=120* (µg/mL) |
| MNL† | 116 (40.2) | 1790 (540) | 4710 (1100) | 16.2 (5.51) |
| PMNL† | 146 (66.0) | 2080 (650) | 10000 (2690) | 81.7 (23.3) |
| LUNG | Cmax (µg/mL) | AUC0–24 (µg∙hr/mL) | AUC0–72 (µg∙hr/mL) | |
| ALVEOLAR CELL‡ | 669 | 7028 | 20403 | - |
| ELF‡ | 3.2 | 17.6 | 131 | - |
| Cmax (µg/g) | AUC0–24 (µg∙hr/g) | AUC0–72 (µg∙hr/g) | ||
| LUNG TISSUE‡ | 37.9 | 505 | 1693 | - |
Following a regimen of 500 mg of azithromycin tablets on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 µg/mL) in the presence of non-inflamed meninges.
Metabolism
In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.
Excretion
Serum azithromycin concentrations following a single 2 g dose of Zmax declined in a polyphasic pattern with a terminal elimination half-life of 59 hours. The prolonged terminal half-life is thought to be due to a large apparent volume of distribution.
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.
Special Populations
Renal Impairment
Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 × 250 mg capsules), the mean Cmax and AUC0–120 were 5.1% and 4.2% higher, respectively in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0–120 were 61% and 35% higher, respectively in subjects with GFR <10 mL/min compared to subjects with normal renal function. (See Renal Impairment (8.6).)
Hepatic Impairment
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.
Pediatric Patients
The pharmacokinetics of azithromycin were characterized following a single 60 mg/kg dose of Zmax in pediatric patients aged 3 months to 16 years. Although there was high inter-patient variability in systemic exposure (AUC and Cmax) across the age groups studied, individual azithromycin AUC and Cmax values in pediatric patients were comparable to or higher than those following administration of 2 g Zmax in adults (Table 4). (See Pediatric Use (8.4).)
| Treatment Group | Pharmacokinetic Parameters | |||
|---|---|---|---|---|
| Cmax (µg/mL) | Tmax* (hr) | AUC(0–24) (µg∙hr/mL) | AUC(0–∞) (µg∙hr/mL) | |
| Empty stomach = dosed with Zmax at least 1 hour before or 2 hours after a meal (Groups I–VI) Fed = dosed with Zmax within 5 minutes of consuming an age-appropriate high-fat breakfast (Group VII) | ||||
| ||||
| Group 1 (N = 6) [3 to 18 months] | 0.74 (0.20) | 3 (3–3) | 6.29 (1.17) | 14.1 (2.16) (n = 3) |
| Group 2† (N = 6) [>18 to 36 months] | 1.88† (0.50) | 3 (3–3) | 19.7† (5.35) | 37.3 (12.9) (n = 5) |
| Group 3 (N = 6) [>36 to 48 months] | 1.23 (0.42) | 3 (3–6) | 12.9 (3.79) | 22.4 (5.96) |
| Group 4 (N = 6) [>48 months to 8 years] | 1.13 (0.34) | 3 (3–6) | 13.0 (4.21) | 22.2 (6.89) |
| Group 5 (N = 6) [>8 to 12 years] | 1.65 (0.38) | 3 (3–6) | 16.0 (4.99) | 30.1 (10.7) |
| Group 6 (N = 6) [>12 to 16 years] | 0.98 (0.35) | 3 (3–6) | 11.0 (4.78) | 21.3 (9.37) |
| Pooled 1–6 (N = 36) [On an empty stomach] | 1.27 (0.53) | 3 (3–6) | 13.1 (5.78) | 25.2 (10.7) (n = 32) |
| Group 7‡ (N = 7) [Fed; 18 months to 8 years] | 1.41 (0.62) | 3 (1.5–3.1) | 7.43 (3.00) | 18.9 (3.57) (n = 3) |
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.
Pharmacokinetic Interaction Studies
A drug interaction study was performed with Zmax and antacids. All other drug interaction studies were performed with azithromycin immediate release (IR) formulations (capsules and tablets, doses ranging from 500 to 1200 mg) 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 5 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 6.
When used at therapeutic doses, azithromycin IR had a minimal effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, nelfinavir, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine (Table 5). Although the drug interaction studies were not conducted with Zmax, similar modest effect as observed with IR formulation are expected since the total exposure to azithromycin is comparable for Zmax and other azithromycin IR regimens. Therefore, no dosage adjustment of drugs listed in Table 5 is recommended when co-administered with Zmax.
Nelfinavir significantly increased the Cmax and AUC of azithromycin following co-administration with azithromycin IR 1200 mg (Table 6). However, no dose adjustment of azithromycin is recommended when Zmax is co-administered with nelfinavir.
Pharmacokinetic and/or pharmacodynamic interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, pharmacokinetic and/or pharmacodynamic interactions with these drugs have been observed with other macrolide products. Until further data are developed, careful monitoring of patients is advised when azithromycin and these drugs are used concomitantly: digoxin, ergotamine or dihydroergotamine, cyclosporine, hexobarbital and phenytoin.
| 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 = 1.00 | |
|---|---|---|---|---|---|
| Mean Cmax | Mean AUC | ||||
| |||||
| Atorvastatin | 10 mg/day × 8 days | 500 mg/day PO on days 6–8 | 12 | 0.83 (0.63 to 1.08) | 1.01 (0.81 to 1.25) |
| Carbamazepine | 200 mg/day × 2 days, then 200 mg BID × 18 days | 500 mg/day PO for days 16–18 | 7 | 0.97 (0.88 to 1.06) | 0.96 (0.88 to 1.06) |
| Cetirizine | 20 mg/day × 11 days | 500 mg PO on day 7, then 250 mg/day on days 8–11 | 14 | 1.03 (0.93 to 1.14) | 1.02 (0.92 to 1.13) |
| Didanosine | 200 mg PO BID × 21 days | 1,200 mg/day PO on days 8–21 | 6 | 1.44 (0.85 to 2.43) | 1.14 (0.83 to 1.57) |
| Efavirenz | 400 mg/day × 7 days | 600 mg PO on day 7 | 14 | 1.04† | 0.95† |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 1.04 (0.98 to 1.11) | 1.01 (0.97 to 1.05) |
| Indinavir | 800 mg TID × 5 days | 1,200 mg PO on day 5 | 18 | 0.96 (0.86 to 1.08) | 0.90 (0.81 to 1.00) |
| Midazolam | 15 mg PO on day 3 | 500 mg/day PO × 3 days | 12 | 1.27 | |
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