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

-------

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

-------------

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

-----------

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. [...]