AZIMAX Tablet Ref.[50468] Active ingredients: Azithromycin

Azithromycin is a macrolide antibacterial drug.

PK/PD relationship

For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.

Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin-based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.

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.

Mechanism of 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 (MLSB phenotype).

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomised, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with 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 with 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 coadministration of 500 mg, 1,000 mg and 1,500 mg azithromycin, respectively.

Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC_0–72 = 4.3 (1.2) mcg∙h/mL; C_max = 0.5 (0.2) mcg/mL; T_max = 2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet

In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2–5) or 3 days (500 mg per day for days 1–3). Due to limited serum samples on day 2 (3-day regimen) and days 2–4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC_{(0–infinity)} for the fitted concentration profile was comparable between the 5-day and 3-day regimens.

Absorption

Bioavailability after oral administration is approximately 37%. Peak concentrations in the plasma are attained 2-3 hours after taking the medicinal product.

In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high-fat meal, food was shown to increase the C_max by 23% but had no effect on the AUC.

When azithromycin suspension was administered with food to 28 adult healthy male subjects, the C_max increased by 56% and the AUC was unchanged.

The AUC of azithromycin was unaffected by co-administration of an antacid containing aluminium and magnesium hydroxide with azithromycin capsules; however, the C_max was reduced by 24%. Administration of cimetidine (800 mg), 2 hours prior to azithromycin, had no effect on azithromycin absorption.

Distribution

Following oral administration, azithromycin is widely distributed throughout the body, with an apparent steady-state volume of distribution of 31 L/kg.

In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma.

Azithromycin has been shown to penetrate into human tissues, including skin, lungs, tonsils, 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 significance of these tissue concentration data is unknown.

Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of non-inflamed meninges.

Concentrations in the infected tissues, such as lungs, tonsils and prostate are higher than the MIC₉₀ of the most frequently occurring pathogens after a single dose of 500 mg.

In experimental in vitro and in vivo studies, azithromycin accumulates in phagocytes; release is promoted by active phagocytosis. In animal models, this process appears to contribute to the accumulation of azithromycin in tissue.

The antimicrobial 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.

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.

Metabolism

In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.

Elimination

Approximately 12% of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 mcg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile, together with 10 metabolites (formed by Nand O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggest that the metabolites do not play a role in the microbiological activity of azithromycin.

Plasma concentrations of azithromycin following single 500 mg oral and intravenous 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.

Specific Populations

Patients with Renal Impairment

Azithromycin pharmacokinetics was 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 C_max and AUC_0-120 increased by 5.1% and 4.2%, respectively in subjects with mild-to-moderate renal impairment (GFR: 10 to 80 mL/min) compared with subjects with normal renal function (GFR >80 mL/min). The mean C_max and AUC_0-120 increased 61% and 35%, respectively, in subjects with severe renal impairment (GFR <10 mL/min) compared with subjects with normal renal function (GFR >80 mL/min).

Patients with Hepatic Impairment

The pharmacokinetics of azithromycin in subjects with hepatic impairment has 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

Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in young adults (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen.

Paediatric 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 paediatric patients (aged 1–5 years and 5–15 years, respectively). The mean pharmacokinetic parameters on day 5 were C_max=0.216 mcg/mL, Tmax=1.9 hours, and AUC_0–24=1.822 mcg∙hr/mL for the 1- to 5-year-old group and were C_max=0.383 mcg/mL, Tmax=2.4 hours, and AUC_0–24=3.109 mcg∙hr/mL for the 5- to 15-year-old group.

In another study, 33 paediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days, of whom 31 patients were evaluated for azithromycin pharmacokinetics following a low-fat breakfast. In this study, azithromycin concentrations were determined over a 24-hour period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. In 17 patients (weighing 41.7 kg or less), a total dose of 60 mg/kg was administered. The following table shows pharmacokinetic data in the subset of paediatric patients who received a total dose of 60 mg/kg.

Single-dose pharmacokinetics in paediatric patients given doses of 30 mg/kg has not been studied.

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 effects 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 C_max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2.

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin:

PO=* 90% CI (confidence interval) not reported.

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs:

PO=* 90% CI not reported

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Carcinogenic potential

Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only and there were no signs indicative of carcinogenic activity.

Mutagenic potential

There was no evidence of a potential for genetic and chromosome mutations in invivo and in-vitro test models.

Reproductive toxicity

In animal studies for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain.

In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.