Zithromax (Pharmacists' 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.

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. [...]

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. [...]

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. [...]