Azithromycin Dihydrate 600 mg Tablet, Film Coated, 30-count — NDC 68094-690-30 (Billing 68094-0690-30)

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.

12.3Pharmacokinetics The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in the following chart: MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. C max (mcg/mL) T max (hr) C 24 (mcg/mL) AUC (mcg∙hr/mL) T½ (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05

2.6AUC 0-24 ; – 4.5 and 250 mg on Days 2 to 5 12 5 0.24 3.2 0.05 2.1 – 6.5 1,200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8 0-last. 40 – %CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4 %CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8 84.5 - %CV (18%) (52%) (26%) (25%) - 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4,763 82.8 - %CV (49%) (28%) (33%) (42%) - - With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy.

However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving 600 mg azithromycin tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

Absorption The 1 gram single - dose packet is bioequivalent to four 250 mg azithromycin capsule. When the oral suspension of azithromycin was administered with food, the C max increased by 46% and the AUC by 14%. The absolute bioavailability of two 600 mg tablets was 34% (CV = 56%).

Administration of two 600 mg tablets with food increased C max by 31% (CV = 43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs = 1.00; CV = 55%). 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. The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH.

However, the extensive distribution of drug to tissues may be relevant to clinical activity. Azithromycin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix. Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder).

As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical importance of these tissue… [Excerpted — this section continues on DailyMed.]

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

12.3Pharmacokinetics The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in the following chart: MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. C max (mcg/mL) T max (hr) C 24 (mcg/mL) AUC (mcg∙hr/mL) T½ (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05

2.6AUC 0-24 ; – 4.5 and 250 mg on Days 2 to 5 12 5 0.24 3.2 0.05 2.1 – 6.5 1,200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8 0-last. 40 – %CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4 %CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8 84.5 - %CV (18%) (52%) (26%) (25%) - 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4,763 82.8 - %CV (49%) (28%) (33%) (42%) - - With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy.

However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving 600 mg azithromycin tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues.

Absorption The 1 gram single - dose packet is bioequivalent to four 250 mg azithromycin capsule. When the oral suspension of azithromycin was administered with food, the C max increased by 46% and the AUC by 14%. The absolute bioavailability of two 600 mg tablets was 34% (CV = 56%).

Administration of two 600 mg tablets with food increased C max by 31% (CV = 43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs = 1.00; CV = 55%). 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. The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH.

However, the extensive distribution of drug to tissues may be relevant to clinical activity. Azithromycin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix. Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder).

As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical importance of these tissue concentration data is unknown. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hr of incubation.

In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Following oral administration of a single 1,200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration remained above 32 mcg/mL, for approximately 60 hr.

The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma C max ratios for males and females were 258 (± 77%) and 175 (± 60%), respectively, and the AUC ratios were 804 (± 31%) and 541 (± 28%), respectively. The clinical relevance of these findings is unknown.

Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (± 49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/mL (± 33%). The mean leuko… [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.

14 CLINICAL STUDIES

14.1Clinical Studies in Patients with Advanced HIV Infection for the Prevention and Treatment of Disease Due to Disseminated Mycobacterium avium Complex (MAC) [see Indications and Usage (1) ] Prevention of Disseminated MAC Disease Two randomized, double-blind clinical trials were performed in patients with CD4 counts < 100 cells/mcL. The first trial (Study 155) compared azithromycin (1,200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcL. The second trial (Study 174) randomized 723 patients to either azithromycin (1,200 mg once weekly), rifabutin (300 mg daily), or the combination of both.

The mean CD4 count was 51 cells/mcL. The primary endpoint in these trials was disseminated MAC disease. Other endpoints included the incidence of clinically significant MAC disease and discontinuations from therapy for drug-related side effects.

MAC bacteremia In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are in the following table: Cumulative Incidence Rate, %: Placebo (n = 89) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 69.7 13.5 6.7 10.1 12 47.2 19.1 15.7 18.0 18 37.1 22.5 18.0

22.5Cumulative Incidence Rate, %: Azithromycin (n = 85) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 84.7 3.5 9.4 2.4 12 63.5 8.2 16.5 11.8 18 44.7 11.8 25.9

17.6The difference in the one - year cumulative incidence rates of disseminated MAC disease (placebo – azithromycin) is 10.9%. This difference is statistically significant (p = 0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference.

In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table: Cumulative Incidence Rate, %: Rifabutin (n = 223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 83.4 7.2 8.1 1.3 12 60.1 15.2 16.1 8.5 18 40.8 21.5 24.2

13.5Cumulative Incidence Rate, %: Azithromycin (n = 223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 85.2 3.6 5.8 5.4 12 65.5 7.6 16.1 10.8 18 45.3 12.1 23.8

18.8Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n = 218) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 89.4 1.8 5.5 3.2 12 71.6 2.8 15.1 10.6 18 49.1 6.4 29.4

15.1Comparing the cumulative one - year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin – azithromycin) in the one - year rates (7.6%) is statistically significant (p = 0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone.

The difference (rifabutin – azithromycin/rifabutin) in the cumulative one - year incidence rates (12.5%) is statistically significant (p < 0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference. In Study 174, sensitivity testing 1 was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin, or the combination.

The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As the efficacy of azithromycin in t… [Excerpted — this section continues on DailyMed.]

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 mg/kg/day 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 mg/kg/day to 30 mg/kg/day (approximately 0.3 to 0.5 times the adult human daily dose of 600 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 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 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 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 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 finding for animals and for humans is unknown.