Zithromax (Compendium)

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Zithromax (Pharmacists' Compendium)

Excerpts from the Compendium of Pharmaceuticals and Specialities, 1999,

Canadian Pharmacists Association, pages 2027-2030:

Zithromax

Azithromycin Dihydrate

Antibiotic

Pharmacology

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Azithromycin, a macrolide antibiotic of the azalide subclass, exerts

its antibacterial action by binding to the 50s ribosomal subunits of

susceptible bacteria and suppressing protein synthesis.

Following oral administration, azithromycin is rapidly absorbed (T max=

2 to 3 hours) and distributed widely throughout the body. Rapid

movement of azithromycin from blood into tissue results in

significantly higher azithromycin concentrations in tissue than in

plasma (up to 50 times the maximum observed concentration in plasma).

The absolute bioavailability is approximately 37%.

When azithromycin capsules were administered with food to 11 adult

healthy male subjects, the rate of absorption (C max) of azithromycin

from the capsule formulation was reduced by 52% and the extent of

absorption (AUC) by 43%. [...] Therefore, azithromycin capsules and

powder for oral suspension should be given 1 hour before or 2 hours

after a meal.

Food does not affect the absorption of azithromycin in the tablet and

the Single Dose 1 g Packet dosage forms. Unlike the capsule and powder

for oral suspension, azithromycin tablets and azithromycin Single Dose

1 g Packet can be taken without regard to meals. Azithromycin tablets

are bioequivalent to the capsule formulation; the azithromycin oral

suspension as a Single Dose 1 g Packet is bioequivalent to four 250 mg

capsules or tablets.

Pharmacokinetics

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Adults: Plasma concentrations of azithromycin decline in a polyphasic

pattern, resulting in an average terminal half-life of 68 hours. The

prolonged half-life is likely due to extensive uptake and subsequent

release of drug from tissues. Over the dose range of 250 to 1000 mg

orally, the serum concentrations are related to dose. The long tissue

half-life and large volume of distribution result from intracytoplasmic

uptake and storage in lysosomal phospholipid complexes. [...]

When studied in healthy elderly subjects from age 65 to 85 years, the

pharmacokinetic parameters of azithromycin capsules 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 occured. There are no pharmacokinetic data

available from studies in hepatically or renally impaired individuals.

Biliary excretion of azithromycin, predominantly as unchanged drug, is

a main route of elimination.

Warnings

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Pseudomembranous colitis has been reported with nearly all

antibacterial agents including azithromycin and may range in severity

from mild to life-threatening. Therefore, it is important to consider

this diagnosis in patients who present with diarrhea subsequent to the

administration of antibacterial agents. Treatment with antibacterial

agents alters the normal flora of the colon and may permit overgrowth

of clostridia. Studies indicate that a toxin produced by C. difficile

is a primary cause of " antibiotic-associated colitis " . After the

diagnosis of pseudomembranous colitis has been established, therapeutic

measures should be initiated. [...]

Precautions

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General: Since liver is the major route of elimination for

azithromycin, the use of azithromycin should be undertaken with caution

in patients with significant hepatic disease.

No dose adjustment is needed in patients with mild renal impairment

(creatinine clearance >40 mL/min), but there are no data regarding

azithromycin usage in patients with more severe renal impairment. Thus

caution should be exercised before prescribing azithromycin in these

patients.

The following adverse events have been reported with macrolide

products: ventricular arrhythmias, including ventricular tachycardia

and torsades de pointes, in individuals with prolonged QT intervals.

Although these adverse events have not been reported in clinical trials

with azithromycin, one AIDS patient dosed at 750 mg to 1 g daily

experienced prolonged QT interval and torsades de pointes.

Pregnancy: Animal studies have demonstrated that azithromycin crosses

the placenta. Safety of azithromycin for use in human pregnancy has not

been established.

Lactation: There are no data on secretion in breast milk. Safety of

azithromycin for use in human lactation has not been established. [...]

Studies evaluating the use of repeated courses of therapy have not been

conducted. Safety data with the use of azithromycin at doses higher

than proposed and for durations longer than recommended are limited to

a small number of immunocompromised children who underwent chronic

treatment.

In animal studies, treatment with azithromycin is associated with

accumulation in various tissues, including the extracranial neural

ganglia (i.e., retina and sympathetic nervous system). Tissue

accumulation is both dose and time dependent, and is associated

microscopically with the development of phospholipidosis

(intra-lysosomal drug phospholipid complexes). The only evidence in

animals that azithromycin is associated with alterations of

intracellular phospholipid metabolism has been the documentation of

small increases in phospholipid content after prolonged treatment (6

months) or exaggerated doses. Phospholipidosis has been observed at

total cumulative doses only 2 multiples of the clinical dose. One month

after withdrawal of treatment the concentration of azithromycin and the

presence of phospholipidosis in tissue, including the retina, is at or

near predose levels.

No data exist in humans in regard to the extent of accumulation,

duration of exposure, metabolism or excretory mechanisms of

azithromycin in neural tissue such as the retina and the cochlea. Rare

cases of hearing loss have been reported (See Adverse Effects). [...]

Drug Interactions

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Antacids: Aluminium and magnesium containing antacids (Maalox) reduce

the peak serum levels but not the extent of azithromycin absorption.

These drugs should not be taken simultaneously. [...]

Adverse Effects

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The majority of side effects observed in controlled clinical trials

involving patients (adults and children) treated with azithromycin were

of a mild and transient nature. Approximately 0.7% of both adult

patients (n= 3812) and children (n= 2878) who had multiple doses of

azithromycin discontinued therapy because of drug related side effects.

Most of the side effects leading to discontinuation were related to the

gastrointestinal tract, e.g., nausea, vomiting, diarrhea or abdominal

pain. Potentially serious side effects including angioedema and

cholestatic jaundice occurred in less than 1% of patients.

Clinical: Multiple-Dose Regimen (Adults and Children): In adult

patients, the most common side effects in patients receiving the

multiple-dose regimen of azithromycin were related to the

gastrointestinal system with diarrhea (4.3%), abdominal pain (2.6%),

vomiting (1.3%) and nausea (3.5%). In children (n= 1944) enrolled in

North American controlled clinical trials in acute otitis media and S.

pyogenes pharyngitis, the type of side effects was comparable to that

seen in adults, with diarrhea/loose stools (5.3%), vomiting (3.6%),

abdominal pain (2.6%), nausea (1%), rash (1%) and headache (1%) the

most frequently reported. [...]