Zithromax (Page 2 of 11)

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 i.v. doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

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 Insufficiency

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 azithromycin, mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0–120 increased 61% and 35%, respectively in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency

The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.

Gender

There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.

Geriatric Patients

When studied in healthy elderly subjects aged 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.

Pediatric Patients

In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 to two groups of pediatric patients (aged 1–5 years and 5–15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax =0.216 µg/mL, Tmax =1.9 hours, and AUC0–24 =1.822 µg∙hr/mL for the 1- to 5-year-old group and were Cmax =0.383 µg/mL, Tmax =2.4 hours, and AUC0–24 =3.109 µg∙hr/mL for the 5- to 15-year-old group.

Two clinical studies were conducted in 68 pediatric patients aged 3–16 years to determine the pharmacokinetics and safety of azithromycin for oral suspension. Azithromycin was administered following a low-fat breakfast.

The first study consisted of 35 pediatric patients treated with 20 mg/kg/day (maximum daily dose 500 mg) for 3 days of whom 34 patients were evaluated for pharmacokinetics.

In the second study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days of whom 31 patients were evaluated for pharmacokinetics.

In both studies, azithromycin concentrations were determined over a 24 hour period following the last daily dose. Patients weighing above 25.0 kg in the 3-day study or 41.7 kg in the 5-day study received the maximum adult daily dose of 500 mg. Eleven patients (weighing 25.0 kg or less) in the first study and 17 patients (weighing 41.7 kg or less) in the second study received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg.

Pharmacokinetic Parameter [mean (SD)] 3-Day Regimen (20 mg/kg × 3 days) 5-Day Regimen (12 mg/kg × 5 days)

n

11

17

Cmax (µg/mL)

1.1 (0.4)

0.5 (0.4)

Tmax (hr)

2.7 (1.9)

2.2 (0.8)

AUC0–24 (µg∙hr/mL)

7.9 (2.9)

3.9 (1.9)

The similarity of the overall exposure (AUC0–∞ ) between the 3-day and 5-day regimens in pediatric patients is unknown.

Single dose pharmacokinetics in pediatric patients given doses of 30 mg/kg have not been studied. (See DOSAGE AND ADMINISTRATION.)

Drug-Drug Interactions

Drug interaction studies were performed with azithromycin 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 1 and the effect of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.

Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. (See PRECAUTIONS — Drug Interactions.)

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin
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
NA — Not Available
Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.
*
- 90% Confidence interval not reported

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 (0.89 to 1.81)

1.26 (1.01 to 1.56)

Nelfinavir

750 mg TID × 11 days

1,200 mg PO on day 9

14

0.90 (0.81 to 1.01)

0.85 (0.78 to 0.93)

Rifabutin

300 mg/day × 10 days

500 mg PO on day 1, then 250 mg/day on days 2–10

6

See footnote below

NA

Sildenafil

100 mg on days 1 and 4

500 mg/day PO × 3 days

12

1.16 (0.86 to 1.57)

0.92 (0.75 to 1.12)

Theophylline

4 mg/kg IV on days 1, 11, 25

500 mg PO on day 7, 250 mg/day on days 8–11

10

1.19 (1.02 to 1.40)

1.02 (0.86 to 1.22)

Theophylline

300 mg PO BID × 15 days

500 mg PO on day 6, then 250 mg/day on days 7–10

8

1.09 (0.92 to 1.29)

1.08 (0.89 to 1.31)

Triazolam

0.125 mg on day 2

500 mg PO on day 1, then 250 mg/day on day 2

12

1.06*

1.02*

Trimethoprim/Sulfamethoxazole

160 mg/800 mg/day PO × 7 days

1,200 mg PO on day 7

12

0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03)

0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03)

Zidovudine

500 mg/day PO × 21 days

600 mg/day PO × 14 days

5

1.12 (0.42 to 3.02)

0.94 (0.52 to 1.70)

Zidovudine

500 mg/day PO × 21 days

1,200 mg/day PO × 14 days

4

1.31 (0.43 to 3.97)

1.30 (0.69 to 2.43)

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS — Drug Interactions.)
Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean Cmax Mean AUC
NA – Not available
Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
*
- 90% Confidence interval not reported

Efavirenz

400 mg/day × 7 days

600 mg PO on day 7

14

1.22(1.04 to 1.42)

0.92*

Fluconazole

200 mg PO single dose

1,200 mg PO single dose

18

0.82(0.66 to 1.02)

1.07(0.94 to 1.22)

Nelfinavir

750 mg TID × 11 days

1,200 mg PO on day 9

14

2.36(1.77 to 3.15)

2.12(1.80 to 2.50)

Rifabutin

300 mg/day × 10 days

500 mg PO on day 1, then 250 mg/day on days 2–10

6

See footnote below

NA

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