Zithromax azithromycin dihydrate 500 mg/5mL Injection, Powder, Lyophilized, For Solution — NDC 0069-0400-10 (Billing 00069-0400-10)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Azithromycin is a macrolide antibacterial drug. [see Microbiology (12.4) ]

12.2Pharmacodynamics Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens ( S. pneumoniae and S. aureus ). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin. Cardiac Electrophysiology QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with oral azithromycin (500 mg, 1,000 mg, and 1,500 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, 1,000 mg and 1,500 mg azithromycin, respectively. Since the mean C max of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean C max of azithromycin following the administration of a 1,500 mg oral dose, it is possible that QTc may be prolonged to a greater extent with IV azithromycin at close proximity to a one hour infusion of 500 mg.

12.3Pharmacokinetics In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean C max ± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC 24 was 9.60 ± 4.80 mcg∙hr/mL. The mean C max , 24-hour trough and AUC 24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ±0.86 mcg∙hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL.

Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2–5 days. Infusion Concentration, Duration Time after starting the infusion (hr) 0.5 1 2 3 4 6 8 12 24 2 mg/mL, 1 hr 500 mg (2 mg/mL) for 2–5 days in community-acquired pneumonia patients. 2.98 ±1.12 3.63 ±1.73 0.60 ±0.31 0.40 ±0.23 0.33 ±0.16 0.26 ±0.14 0.27±0.15 0.20 ±0.12 0.20 ±0.15 1 mg/mL, 3 hr 500 mg (1 mg/mL) for 5 days in healthy subjects.

0.91±0.13 1.02 ±0.11 1.14 ±0.13 1.13 ±0.16 0.32 ±0.05 0.28 ±0.04 0.27±0.03 0.22 ±0.02 0.18 ±0.02 Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in C max but a 61% increase in AUC 24 reflecting a threefold rise in C 24 trough levels. Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, C max , trough level, and AUC 24 were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg∙hr/mL, respectively.

These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (C max : 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC 24 : 5 mcg∙hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.

Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix. Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients.

Approximate… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Azithromycin is a macrolide antibacterial drug. [see Microbiology (12.4) ]

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.

12.3Pharmacokinetics In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean C max ± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC 24 was 9.60 ± 4.80 mcg∙hr/mL. The mean C max , 24-hour trough and AUC 24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ±0.86 mcg∙hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL.

Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2–5 days. Infusion Concentration, Duration Time after starting the infusion (hr) 0.5 1 2 3 4 6 8 12 24 2 mg/mL, 1 hr 500 mg (2 mg/mL) for 2–5 days in community-acquired pneumonia patients. 2.98 ±1.12 3.63 ±1.73 0.60 ±0.31 0.40 ±0.23 0.33 ±0.16 0.26 ±0.14 0.27±0.15 0.20 ±0.12 0.20 ±0.15 1 mg/mL, 3 hr 500 mg (1 mg/mL) for 5 days in healthy subjects.

0.91±0.13 1.02 ±0.11 1.14 ±0.13 1.13 ±0.16 0.32 ±0.05 0.28 ±0.04 0.27±0.03 0.22 ±0.02 0.18 ±0.02 Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in C max but a 61% increase in AUC 24 reflecting a threefold rise in C 24 trough levels. Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, C max , trough level, and AUC 24 were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg∙hr/mL, respectively.

These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (C max : 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC 24 : 5 mcg∙hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval.

Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix. Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients.

Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were less than 0.01 mcg/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.

Elimination Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenous-dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hr was about 11% after the 1st dose and 14% after the 5th dose.

These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration. 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 1,000 mg dose of az… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens ( S. pneumoniae and S. aureus ). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin. Cardiac Electrophysiology QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with oral azithromycin (500 mg, 1,000 mg, and 1,500 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, 1,000 mg and 1,500 mg azithromycin, respectively. Since the mean C max of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean C max of azithromycin following the administration of a 1,500 mg oral dose, it is possible that QTc may be prolonged to a greater extent with IV azithromycin at close proximity to a one hour infusion of 500 mg.

14 CLINICAL STUDIES

14.1Community-Acquired Pneumonia In a controlled trial of community-acquired pneumonia performed in the U.S., azithromycin (500 mg as a single daily dose by the intravenous route for 2 to 5 days, followed by 500 mg/day by the oral route to complete 7 to 10 days therapy) was compared to cefuroxime (2,250 mg/day in three divided doses by the intravenous route for 2 to 5 days followed by 1,000 mg/day in two divided doses by the oral route to complete 7 to 10 days therapy), with or without erythromycin. For the 291 patients who were evaluable for clinical efficacy, the clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 277 patients seen at 10 to 14 days post-therapy were as follows: Clinical Outcome Azithromycin Comparator Cure 46% 44% Improved 32% 30% Success (Cure + Improved) 78% 74% In a separate, uncontrolled clinical and microbiological trial performed in the U.S., 94 patients with community-acquired pneumonia who received azithromycin in the same regimen were evaluable for clinical efficacy.

The clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 84 patients seen at 10 to 14 days post-therapy were as follows: Clinical Outcome Azithromycin Cure 60% Improved 29% Success (Cure + Improved) 89% Microbiological determinations in both trials were made at the pre-treatment visit and, where applicable, were reassessed at later visits. Serological testing was done on baseline and final visit specimens. The following combined presumptive bacteriological eradication rates were obtained from the evaluable groups: Combined Bacteriological Eradication Rates for Azithromycin: (at last completed visit) Azithromycin S. pneumoniae 64/67 (96%) Nineteen of twenty-four patients (79%) with positive blood cultures for S. pneumoniae were cured (intent-to-treat analysis) with eradication of the pathogen.

H. influenzae 41/43 (95%) M. catarrhalis 9/10 (90%) S. aureus 9/10 (90%) The presumed bacteriological outcomes at 10 to 14 days post-therapy for patients treated with azithromycin with evidence (serology and/or culture) of atypical pathogens for both trials were as follows: Evidence of Infection Total Cure Improved Cure + Improved Mycoplasma pneumoniae 18 11 (61%) 5 (28%) 16 (89%) Chlamydia pneumoniae 34 15 (44%) 13 (38%) 28 (82%) Legionella pneumophila 16 5 (31%) 8 (50%) 13 (81%)

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 0.4 to 0.6 times the adult daily dose of 500 mg 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.

13.2Animal Toxicology and/or Pharmacology Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple oral doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment.

Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6 times the observed C max of 0.821 mcg /mL at the adult dose of 2 g.) Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg /mL (1.2 times the observed C max of 0.821 mcg /mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg based on body surface area.

It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg/mL, approximately 1.5 times the C max of 1.27 mcg/mL at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg/mL, approximately 3 times the pediatric dose C max . The significance of the findings for animals and for humans is unknown.