ZMAX- azithromycin dihydrate_powder, for suspension

Azithromycin is a macrolide antibacterial drug. [See Clinical Pharmacology (12. 4) 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 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. 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 (C max 0en dash24 Table 2. Mean (SD) Pharmacokinetic Parameters for Azithromycin on Day 1 Following the Administration of a Single Dose of 2 g Zmax or 1. 5 g of Azithromycin Tablets Given over 3 Days (500 mg/day) or 5 Days (500 mg on Day 1 and 250 mg on Days 2en dash5) to Healthy Adult Subjects Pharmacokinetic Parameter Zmax, 3-day and 5-day regimen parameters obtained from separate pharmacokinetic studies Azithromycin Regimen Zmax [N=41] N = 21 for AUC 0en dashinfinity 1/2 3-day C max max 0en dash24 [N=12] 5-day [N=12] paragraph Total AUC for the 1-day, 3-day and 5-day regimens SD = standard deviation max max max 1/2 C max 0. 434 T max Median (range) (hr) 5. 5 AUC 0en dash24 (mcg∙hr/mL) 8. 60 AUC 0en dashinfinity (mcg∙hr/mL) 20. 9 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 hr 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 C max, 0en dash72 max 0en dash72 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 mcg/mL to 7% at 2 mcg/mL. Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31. 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 (AUC 0en dash120 0en dash72 Table 3. Azithromycin Exposure Data in White Blood Cells and Lung Following a 2 g Single Dose of Zmax in Adults A single 2 g dose of Zmax Abbreviation: WBC: white blood cells; MNL: mononuclear leukocytes; PMNL: polymorphonuclear leukocytes; ELF: Epithelial lining fluid WBC C max AUC 0en dash24 AUC 0en dash120 C t=120 Azithromycin concentration at 120 hr after the start of dosing MNL Data are presented as mean (standard deviation) 116 (40. 2) 1790 (540) 4710 (1100) 16. 51) PMNL 146 (66. 0) 2080 (650) 10000 (2690) 81. 3) LUNG C max AUC 0en dash24 AUC 0en dash72 ALVEOLAR CELL C max 669 7028 20403 - ELF 3. 6 131 - C max AUC 0en dash24 AUC 0en dash72 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 mcg/mL) in the presence of non-inflamed meninges. Metabolism In vitro in vivo 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 hr. 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. Specific Populations Patients with 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 C max 0en dash120 max 0en dash120. [See Use in Specific Populations Renal Impairment (8. 6) Patients with 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 C max max [See Use in Specific Populations (8. Mean (SD) Pharmacokinetic Parameters for Azithromycin Following Administration of a Single Dose of Zmax (60 mg/kg, maximum dose of 2 g) to Pediatric Subjects Aged 3 Months to 16 Years Treatment Group Pharmacokinetic Parameters C max (mcg/mL) T max Median (range) presented only for T max (hr) AUC (0en dash24) (mcg∙hr/mL) AUC (0en dashinfinity) (mcg∙hr/mL) Empty stomach = dosed with Zmax at least 1 hr before or 2 hr after a meal (Groups Ien dashVI) Fed = dosed with Zmax within 5 minutes of consuming an age-appropriate high-fat breakfast (Group VII) Group 1 (N = 6) 0. 20) 3 (3en dash3) 6. 16) Group 2 High mean values were driven by 2 subjects with high exposure 1. 88 3 (3en dash3) 19. 9) Group 3 (N = 6) 1. 42) 3 (3en dash6) 12. 96) Group 4 (N = 6) 1. 34) 3 (3en dash6) 13. 89) Group 5 (N = 6) 1. 38) 3 (3en dash6) 16. 7) Group 6 (N = 6) 0. 35) 3 (3en dash6) 11. 37) Pooled 1en dash6 (N = 36) 1. 53) 3 (3en dash6) 13. 7) Group 7 One subject vomited immediately after dosing and discontinued from the study 1. 57) Male and Female Patients 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. Drug 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 C max 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, colchicine, ergotamine or dihydroergotamine, cyclosporine, hexobarbital and phenytoin. Drug Interactions: Pharmacokinetic Parameters of Co-administered Drugs in the Presence of Azithromycin Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin Refers to azithromycin capsules and tablets unless specified n Ratio (with/without Azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1. 00 Mean C max Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6en dash8 12 0. 01 Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16en dash18 7 0. 96 Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8en dash11 14 1. 02 Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8en dash21 6 1. 14 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. 01 Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0. 90 Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1. 26 Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0. 85 Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1. 92 Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, then 250 mg/day on days 8en dash11 10 1. 02 Theophylline 300 mg orally twice a day for 15 days 500 mg orally on day 6, then 250 mg/day on days 7en dash10 8 1. 08 Triazolam 0. 125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1. 02 Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 0. 87 Zidovudine 500 mg/day orally for 21 days 600 mg/day oraly for 14 days 5 1. 94 Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1. Drug Interactions: Pharmacokinetic Parameters of Azithromycin in the Presence of Co-administered Drugs Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin Refers to azithromycin capsules and tablets unless specified n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1. 00 Mean C max Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1. 92 90% confidence interval not reported Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0. 07 Nelfinavir 750 mg three times a day 11 days 1,200 mg orally on day 9 14 2. 12 Aluminum and Magnesium hydroxide 20 mL regular strength, single dose 2 g Zmax, single dose 39 0. 99 Mechanism of Action Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit. Resistance Azithromycin demonstrates cross resistance with erythromycin. The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides and streptogramin B (MLS B Azithromycin has been shown to be active against the following microorganisms, both in vitro [See Indications and Usage (1) Gram-Positive Bacteria Streptococcus pneumoniae Gram-Negative Bacteria Haemophilus influenzae Moraxella catarrhalis "Other" Bacteria Chlamydophila pneumoniae Mycoplasma pneumoniae Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.

Zmax is a macrolide antimicrobial drug indicated for mild to moderate infections caused by designated, susceptible bacteria: 1. 1 Limitations of Use Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors ( 1. 2 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. 3 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 Streptococcus pneumoniae Community-acquired pneumonia in adults and pediatric patients six months of age or older due to Chlamydophila pneumoniae Haemophilus influenzae Mycoplasma pneumoniae Streptococcus pneumoniae, [See Use in Specific Populations (8. 4) 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: 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 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). 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). Zmax Pediatric Dosage Guidelines: 1-dose regimen Dosing Calculated on 60 mg/kg as a single dose for Children <34 kg To ensure accurate dosing, a dosing spoon, medicine syringe, or cup is recommended. Weight 27 mg/mL Dose Kg Dose Volume (mg) (mL) 5 270 10 7 405 15 9 540 20 11 675 25 14 810 30 16 945 35 18 1080 40 20 1215 45 23 1350 50 25 1485 55 27 1620 60 30 1755 65 32 1890 70 >=34 2000 Consume entire contents of bottle 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. 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.

The following clinically significant adverse reactions are described elsewhere in labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) [see Warnings and Precautions (5. 3) [see Warnings and Precautions (5. 4) [see Warnings and Precautions (5. 5) Clostridioides difficile- [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 7) Most common adverse reactions (incidence >=1%) are diarrhea/loose stools, nausea, abdominal pain, headache, and vomiting. 2 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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: Gastrointestinal Genitourinary Nervous system: General: Allergic: Special senses 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 of Zmax. In a trial 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 hr 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 trial 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 trial 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: Digestive: Hematologic and lymphatic Nervous system Respiratory: Skin and appendages: Special senses: Urogenital: 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 Cardiovascular: Gastrointestinal: General: Genitourinary: Hematopoietic: Liver/biliary: [See Warnings and Precautions (5. 2) Nervous system: Psychiatric: Skin/appendages: Special senses: 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: Adults: Laboratory abnormalities with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate. Laboratory abnormalities 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: Laboratory abnormalities 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.

Hypersensitivity to azithromycin, erythromycin, or any macrolide or ketolide drug. 1 History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. 2 Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide drug. Zmax is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

5 Risk Summary Available data from published literature and postmarketing experience over several decades with azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data (see Data The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in pregnant women. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications. Animal Data Azithromycin administered during the period of organogenesis did not cause fetal malformations in rats and mice at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface area, this dose is approximately equivalent to one or one-half of, respectively, the single adult human oral dose of 2 g. In rabbits administered azithromycin at oral doses of 10, 20, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food consumption were observed in all groups; no evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is estimated to be 0. 4 times an adult human oral dose of 2 g based on body surface area. In a pre- and postnatal development study, azithromycin was administered orally to pregnant rats from day 6 of pregnancy until weaning at doses of 50 or 200 mg/kg/day. Maternal toxicity (reduced food consumption and body weight gain; increased stress at parturition) was observed at the higher dose. Effects in the offspring were noted at 200 mg/kg/day during the postnatal development period (decreased viability, delayed developmental landmarks). These effects were not observed in a pre- and postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day 15 of pregnancy until weaning. Risk Summary Azithromycin is present in human milk (see Data (see Clinical Considerations Clinical Considerations Advise women to monitor the breastfed infant for diarrhea, vomiting, or rash. Data Azithromycin breastmilk concentrations were measured in 20 women after receiving a single 2 g oral dose of azithromycin during labor. Breastmilk samples collected on days 3 and 6 postpartum as well as 2 and 4 weeks postpartum revealed the presence of azithromycin in breastmilk up to 4 weeks after dosing. In another study, a single dose of azithromycin 500 mg was administered intravenously to 8 women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours. Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been established. Community-Acquired Pneumonia Chlamydophila pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae Streptococcus pneumoniae. [See Dosage and Administration (2. 2) Adverse reactions (6) Clinical Pharmacology (12. 3) Acute bacterial sinusitis: 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) 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) 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.

2 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) 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. 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.

OVERDOSAGE
Adverse reactions experienced at 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.
NONCLINICAL TOXICOLOGY
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. 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. 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. , 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 C max max 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 C max max The significance of the finding for animals and for humans is unknown.
CLINICAL STUDIES
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. Table 7: Clinical Response in Patients with Acute Bacterial Maxillary Sinusitis ZMAX LEVOFLOXACIN RESPONSE AT TOC N = 255 N = 254 CURE 241 (94. 5%) 236 (92. 9%) FAILURE 14 (5. 1%) Clinical response by pathogen in the Bacteriologic Per Protocol population is presented below. Table 8: Clinical Response by Pathogen in Patients with Acute Bacterial Maxillary Sinusitis Zmax Levofloxacin Pathogen N Cure N Cure S. pneumoniae 37 36 (97. 3%) 39 36 (92. influenzae 27 26 (96. 3%) 30 30 (100. catarrhalis 8 8 (100. 0%) 11 10 (90. 9%) 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. Table 9: Clinical Response at Test of Cure (TOC) in Patients with Community-Acquired Pneumonia Zmax Comparator Zmax vs. Clarithromycin extended-release N=202 N=209 Cure 187 (92. 6%) 198 (94. 7%) Failure 15 (7. 3%) Zmax vs. Levofloxacin N=174 N=189 Cure 156 (89. 7%) 177 (93. 7%) Failure 18 (10. 3%) Clinical response by pathogen in the Bacteriologic Per Protocol population, across both studies, is presented below: Table 10: Clinical Response by Pathogen in Patients with Community-Acquired Pneumonia Pathogen Zmax Comparators N Cure N Cure S. pneumoniae 33 28 (84. 8%) 39 35 (89. influenzae 30 28 (93. 3%) 34 31 (91. pneumoniae 40 37 (92. 5%) 53 50 (94. pneumoniae 33 30 (90. 9%) 39 38 (97.
Patient Information
Read the Patient Information that comes with Zmax registered What is Zmax? Zmax is an antibiotic that kills certain bacteria. Zmax is dosed differently from other antibiotics. You take just one dose, one time Zmax is used in adults and in children over the age of 6 months against bacteria to treat certain kinds of pneumonia (lung infections) Zmax is used in adults against bacteria to treat sinus infections. Zmax has not been studied in children under 6 months of age. Who should not take Zmax? o o Talk with your healthcare provider or pharmacist if you have questions about your medicine allergies. Before you start Zmax Tell your healthcare provider about all your or your child''s medical problems Contact your healthcare provider immediately if you are giving Zmax to a young child (less than 6 weeks of age) and he or she vomits or becomes irritable when fed. Tell your healthcare provider about all the medicines you take, Zmax and other medicines may affect each other causing side effects. Zmax may affect the way other medicines work, and other medicines may affect how Zmax works. Especially tell your healthcare provider if you take: Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider or pharmacist when you get a new prescription. Do I need to prepare Zmax? liquid form, it is ready to take. dry powder, you must add water to the bottle before you take it. How do I take Zmax? How will I know Zmax is working? Zmax needs time to work, so you or your child may not feel better right away. If you or your child''s symptoms do not get better in a few days, call your healthcare provider. What are the possible side effects of Zmax? Zmax may cause serious side effects. These happened in a small number of patients. Call your healthcare provider right away or get emergency treatment if you or your child have any of the following: Serious allergic reaction or serious skin reaction: These symptoms could go away and then come back. Diarrhea: Serious heart rhythm changes that can be life-threatening, including heart stopping (cardiac arrest), QT prolongation, torsades de pointes, feeling that your heart is pounding or racing (palpitations), chest discomfort, or irregular heartbeat: o o o o The most common side effects in adults The most common side effects in children Tell your healthcare provider if you have any side effects that bother your or your child, or that does not go away. These are not all of the possible side effects with Zmax. For a list of all reported side effects, ask your healthcare provider or pharmacist. General information about Zmax Healthcare providers sometimes prescribe medicines for conditions that are not in the patient leaflets. Do not use Zmax for anything other than what your healthcare provider prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet is a summary of the most important information about Zmax. For more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Zmax that is written for healthcare professionals. For more information, go to our website at www. com or call 1-800-438-1985. What is in Zmax? Active ingredient: azithromycin dihydrate Brand names are registered trademarks of their respective owners. This product''s label may have been updated. For current full prescribing information, please visit www. com This Patient Information has been approved by the U. Food and Drug Administration.

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