Clinical toleration and safety of azithromycin

Clinical Toleration and Safety of Azithromycin SCOT HOPKINS, M.D., GKI~~,-I, Connecticut

The toleration and safety profile of the azalide antibiotic, azithromycin, has been assessed in 3,995 patients aged 2-94 (mean, 36) years, com- prising 1,644 females and 2,351 males. Patients with infections of the respiratory tract or skin/skin structure received 1.5 g azithromycin over 5 days; patients with urethritis/cervicitis caused by Chlamydia were treated with 1 g as a single dose. Assessments of side effects and laboratory safety test abnormalities were made pretreatment and approximately 7-14 and 30 days after the start of therapy. Twelve standard antibiotics have been used for comparison. Overall, side effects were recorded in 12.0% of patients, significantly less (p CO.05) than with comparative drugs (14.2%). The most common side effects were diarrhea (3.6%), abdominal pain (2.5%), and other gastrointestinal symptoms. Ninety-three percent of side effects were classed as mild or moderate, and only 0.7% of patients withdrew from treatment, significantly less (p CO.001) than with comparative agents (2.6%). The frequency of side effects was not affected by patient age. Azith- romycin had no marked or consistent effect on laboratory safety parameters. Treatment- related laboratory abnormalities were rare, the most common being transient increases of ALT and AST in 1.7% and 1.5% of patients, respectively. Specific tests revealed no neurologic, audiometric, or ophthalmologic abnormalities, or evidence of phospholipidosis. There were no pharmacokinetic interactions observed with theophylline, warfarin, cimetidine, carbamazepine, or methylprednisolone, but coadministration with food altered the absorption of the drug. Coadministration with antacids de- creased the peak serum concentration of azithromycin, but did not affect its overall absorption. Azithromycin was well tolerated in the presence of a wide variety of concurrent illnesses and medications.

From Pfizer Central Research, Groton, Connecticut. Requests for reprints should be addressed to Scott Hopkins, M.D., Pfizer

Central Research, Eastern Point Road, Groton, Connecticut 06340.

A zithromycin is a new, acid-stable, 15-mem- bered ring azalide antibiotic that has been de-

veloped for 5-day, oral treatment of bacterial infections of the upper and lower respiratory tracts (caused by organisms such as Streptococcus pneu- moniae, Haemophilus injluenxae, and Streptococ- cus pyogenes), shin and skin structure (caused by pathogens including Staphylococcus aureus and S. pyogenes), and single-dose oral therapy of uncom- plicated genital Chlamydial infections. After oral administration, the drug is well absorbed and widely distributed, penetrating into and maintain- ing high levels in a wide variety of tissues Cl]. Tis- sue concentrations, often l-10 pg/g, greatly exceed the corresponding serum levels, and gradual re- lease from the tissues leads to slow excretion. Toxi- cology studies in animals revealed no major abnormalities, the principal findings being phospholipidosis in a variety of cells and changes in hepatic parameters at high and prolonged dosages. In humans, phospholipidosis is not observed.

After toleration (Phase I) studies in healthy vol- unteers, research proceeded to establish the safety and efficacy of azithromycin in a limited number of patients (Phase II), subsequently expanding the program into larger numbers of patients (Phase III). This article reports the incidence and severity of side effects and laboratory test abnormalities in the Phase II and III studies that were carried out in the United States and 13 countries in Europe.

PATIENTS AND METHODS Data from 3,995 patients (Table I) treated with

azithromycin are presented. Diagnoses included a variety of bacterial infections, principally of the upper respiratory tract (29%), lower respiratory tract (27%), skin/skin structure (22%), and ure- thritiskervicitis (18%). Most (94%) adult patients with infections of the respiratory tract or skin/skin structure received a total dosage of 1.5 g azithromycin over 5 days in capsules (day 1, 500 mg; days 2-5, 250 mglday, all as once-a-day doses); the remainder received the same total dosage in a shorter regimen. Most patients (82%) with urethritis or cervicitis received a single dose of 1 g azithromycin; the remainder received 1 g over a few days. Patients less than 15 years of age received a total dosage of 30 mglkg body weight of

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azithromycin aqueous suspension over 5 days (day 1, 10 mg/kg; days 2-5, 5 mg/kg/day, all as once- daily doses). All studies were comparative against standard agents (penicillins, penicillin derivatives, cephalosporins, and macrolides) in regimens that were in accordance with the manufacturers’ recom- mendations.

In general, patients were assessed immediately pretreatment (baseline), once or twice in the period ‘7-14 days after the start of treatment, and again about 30 days after the start of treatment. Investi- gators assessed the severity and possible relationship to study drug therapy of any side effects observed or spontaneously volunteered by the patients, and all effects occurring during treatment or within 35 days after the end of therapy are included in this report. Analyses include all side effects reported to be due or possibly due to treatment, along with those of unknown relationship to therapy and those for which no comment on causality was made.

A battery of approximately 30 laboratory tests (hematology, biochemistry, urinalysis) included a complete blood count, serum tests of hepatic and renal function, serum electrolytes, cholesterol, tri- glycerides, uric acid, and fasting glucose. All values outside the limits of normality recorded between baseline and 35 days after the start of therapy were reviewed and classified as follows: transient and unrelated to study drug therapy; due to laboratory error; due to concurrent or intercurrent disease; due to concomitant therapy; clinically insignificant; or related to study treatment. Abnormalities dis- cussed in this article represent those in the latter category.

All statistical comparisons were performed as two-tailed tests, with significance set at p ~0.05. An approximation to Fisher’s exact test was used to compare incidences of side effects between azithromycin and comparative drugs.

SIDE EFFECTS Incidence and Nature

Side effects were recorded in 430 (12.0%) of 3,995 patients treated with azithromycin (Table II). The majority of these effects were classified by the investigators as of unknown relationship to azithromycin, with 22% being classed as definitely drug- related. Among 3,108 patients treated with comparative antibiotics, side effects were recorded in 442 (14.2%), a significantly higher incidence than with azithromycin (p ~0.05). Of those side effects, 37% were classified by investigators as definitely drug-related (p ~0.05).

A wide variety of side effects were recorded (Table II). The most common were associated with the gastrointestinal tract (9.6% of patients) and the

TABLE I Total Patient Population Treated with Azithromycin

Male Female

2;: 1,213 188 36.9

2-94

Total

3,995

29

3~~ 1451 36.0

2-94

Number patients Age lvead

2-5 5-14 15-64 >65

Mean age Age range

TABLE II Nature and Incidence of Side Effects

Azithromycin

Pakb %

Number assessed 3,995 Number with side effects 480 12.0 Number withdrawn due to

side effects 24 0.7* Organ systemS

Autonomic nervous E

0.2 Cardiovascular 0.1 Central and peripheral nervous Gastrointestinal 3;; !E

Abdominal pain Diarrhea 1; ::i Nausea 105 Vomiting 30 a2f

io5 Liverlbiliary 2 Metaboliclnutriiional Musculoskeletal i

co.05 0.1

Psychiatric 21 Reproductive 8 i:; Respiratory Skin 2:

0.2 0.6

$ec; senses5 i

0.2

Vaginitis General :i

LA: 0.6

‘ercentage of 3,443 multiple-dose patients. Wentage of 3,011 multiple-dose patients. Some patients had more than one side effect. jight, hearing, smell, taste.

N’T:he e

Pakts %

14.2

2.6t

0.2 0.2 1.2

12.8

i:; 3.5 1.4 0.06

ao.1

i; 0.1 1.5

i:i6 1.3 0.5

SYMPOSIUM ON TISSUE-DIRECTED ANTIBIOTIC THERAPY I HOPKINS

central and peripheral nervous system (1.3%, pre- dominantly headache and/or dizziness, or both). Side effects involving other organ systems were reported by less than 1% of patients. Gastrointesti- nal disturbances also made up the greatest propor- tion of side effects reported by patients taking comparative agents. Skin rashes and vaginitis were more common than in the azithromycin group. The most frequent individual side effects of azithromycin, and the only ones with an incidence of more than l%, were diarrhea (3.6%), nausea (2.6%), and abdominal pain (2.5%). There was no case of pseudomembranous colitis. Similar results were recorded for the comparative drugs, with a predominance of nausea and diarrhea.

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TABLE III

Premature Discontinuations Due to Side Effects

AseM

Azithromycin All comparative agents AmoxicilWprobenecid Erythromycin ~tn/i; v

Amoxicillin Cephalexin Doxycycline , /nnn,

Total Discontinuations

2413,443 79/3,011 5133

291491 16/631 61245

111574 41305 l/450

Incidence (%I

;:;

15.2 5.9 2.5 2.4

1.9

i:;

Severity and Withdrawals Of 634 side effects reported by azithromycin pa-

tients, 377 (59%) were classified as of mild severity, 215 (34%) as moderate, and 42 (7%) as severe. Equivalent figures for all comparative drugs were 48%, 38%, and 14%, respectively. More than half of the 42 azithromycin side effects judged as severe involved the gastrointestinal system, with abdominal pain (nine), diarrhea (five), and nausea (four) the most frequent. In addition, severe dizziness, headache, and fatigue were each reported for three patients, and cutaneous effects for four. The majority of severe side effects associated with comparative agents also involved the gastrointestinal system.

Among 3,443 azithromycin patients scheduled to receive multiple-dose therapy, treatment was discontinued because of side effects in 24 (0.7%). This was significantly less than for comparative agents (p <O.OOl), where treatment was discontinued in ‘79 (2.6%) of 3,011 multiple-dose patients (Table II). Of the 24 azithromycin patients withdrawn from treatment, 18 had gastrointestinal symptoms, generally diarrhea and nausea, sometimes accompanied by vomiting or abdominal pain. Only five patients withdrew because of side effects classified as severe: vomiting (one); abdominal pain, nausea, and vomiting’(one); diarrhea (one); headache (one); and urticaria (one). Overall, of the 24 withdrawals from azithromycin therapy, 12 were considered to be definitely drug-related and the others were of unknown relationship.

For the comparative antibiotics, the incidence of discontinuations due to side effects is shown in Table III; in comparison, the percentage discontin- uation in the azithromycin population was among the lowest. Because many of the comparative agents were administered for a longer duration than azithromycin, discontinuations from days l-5 were also compared. In almost all instances, there were fewer discontinuations after a full course of

azithromycin than a partial course of a comparative agent (Table III).

Comparison with Other Drugs Frequencies of all side effects, and of the four

principal gastrointestinal complaints and skin rashes recorded during comparative studies, are given in Table IV. Overall, clinical toleration of azithromycin was comparable or superior to that of other drugs and was markedly superior to that of the macrolide erythromycin.

Effect of Patient Age Of 451 patients aged 65 years or more (mean,

72.5 years), 42 (9.3%) reported side effects. These included 2 of 24 (8.3%) subjects .aged 85 years or more (mean, 88.0 years). These frequencies are lower than those recorded in thae total azithromycin population (12.0%), due mainly to lower incidences of abdominal pain and nausea; the frequency of diarrhea was not reduced. Limited safety data were obtained for 497 patients aged 14 years or less, including 29 under the age of 5 years; 27 (5.4%) reported side effects, an incidence much lower than in the total population. More than 80% of side effects in children were gastrointestinal, but only diarrhea (1.8%) and vomiting (1.2%) occurred with a frequency of more than 1%. Additional studies in the pediatric age group are ongoing to define safety and efficacy better in this population.

ABNORMALITIES IN LABORATORY TESTS Incidence and Nature

As in most clinical studies, abnormal laboratory values were recorded before, during, and after treatment. The vast majority were due to underly- ing diseases, concomitant medications, or intercurrent illnesses. Azithromycin did not have a major or consistent effect on any of the laboratory safety tests, and clinically significant abnormalities, both total and those judged to be possibly related to study drug treatment, occurred in comparable pro- portions of azithromycin patients and those who received comparative agents. The incidence of treatment-related abnormalities in indicators of hepatic, hematologic, and renal function, and serum electrolytes, is shown in Table V. The frequency of such abnormalities exceeded 1% only for ALT (1.7%), AST (1.5%), and neutrophil(l.5%) and leu- kocyte (1.1%) counts. The significance of the changes in neutrophil count is not clear; most patients had reduced neutrophil counts, but some developed neutrophilia. These effects were transient.

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TABLE IV

Incidence of Side Effects with Azithromycin and Comparative Drugs

Side Effects* (%)

Drug

Azithromycin Amoxicillin Amoxicillinlprobenecid AmoiciWorobenecid

Patients Assessed

3,995 514 iz

All Diarrhea

12.0 3.6 12.2 4.5 54.5 9.1

4.7 0

Abd;wnal

2.5 0.9 3.0 0

Nausea

2.6 1.7 6.1 1.2

Vomiting

0.8 0.5 i

Rash

0.2 1.6 6.0 0

Ambxicillit&lawlanic acid 129 13.2 8.5 1.6 Cefaclor 245 16.7 5.7 1.2 Y.5

Cephalexin 305 8.5 1.3 0 Cloxacillin 105 11.4 5.7 1.9 ;:i

1.6 0.8 0.4 0.4 03 1.0 1.9 1.0

Doxycycline 450 15.8 0.7 2.9 6.0 0.2 Erythromycin 491 20.4 5.3 6.9

;I 0.6

Penicillin V 630 12.9 3.7 1.4 ;:: 1.3 0.6

*Some patients had more than one side effect.

Marked Abnormalities Marked abnormalities were defined as increases

to >3 times the upper limit of normal for hepatic enzymes or to >50% above this limit for renal function tests, and decreases to ~50% of the lower limit of normal for hematologic parameters or <75% of this limit for serum electrolytes. Taking all abnormalities, regardless of possible causality, a frequency exceeding 0.5% was recorded only for ALT (1.2%) and AST (0.70/o), whereas corresponding figures for the combined comparative agents were 1.3% and 0.5%, respectively.

Among 3,995 patients treated with azithromycin, there were 13 deaths: four patients died while on therapy and nine died in the 35 days after complet- ing treatments. None of the deaths was attributed to drug toxicity. Two deaths, in studies outside the United States, were attributed to inadequate therapeutic response and the others to concomitant or intercurrent disease. In the former group, one patient was a 71-year-old man with pneumonia due to Pseudomonas putida resistant to multiple antibiotics, including azithromycin, who died 7 days after the course of therapy was completed. The second death occurred in a 70-year-old woman with pneumonia who was severely hypoxic on admission and who died of cardiac arrest 36 hours later. All cul- tures were negative and no autopsy was performed.

In 3,108 patients treated with comparative agents, there were 18 deaths, five during therapy and 13 after therapy was complete. None of the deaths with comparative agents was attributed to inadequate therapeutic response.

Withdrawals No course of treatment with azithromycin was

terminated prematurely because of drug-related abnormalities in laboratory test values. However,

TABLE V

Incidence of Treatment-Related laboratory Abnormalities after Treatment with Azithromycin or Comparative Drugs

Parameter

Aziiromycin Comparative Drugs

Number Number Assessed Abnormal (%) Assessed Abnormal (%)

ALT [SGFT) 3;n3 1.7 2,828 2.5

AST (SGOT) 3,840 2,909 Total bilirubin 3,810 8 2,882 Al Alkaline phosphatase 3,841 0.3 2,909 0.4 Netirophik 3,785 1.5 2,875 1.1

F;iheypd cells 3,843 3,815 0.2 1.1 2,910 2,894 0.9 0.03 Hemoglobin 3% 0.1 2,909 0.2 Blood urea nitrogen , 0.4 g4nne I 3;w

3,707 Potassium 3,803

0.3

a02

two patients (0.06%) were withdrawn from subse- quent treatment with placebo, which they were receiving as part of a double-blind study involving a comparative agent with a longer duration of therapy than azithromycin. One was withdrawn because of a marked elevation in ALT; the other, who had abnormally high ALT pretreatment, was withdrawn when this transaminase rose further and AST also increased to an abnormal concentration. Treatment with cefaclor was terminated prematurely in one patient (0.03% of total comparative group) because of abnormally high concentrations of AST, ALT, gamma-glutamyltransferase, and alkaline phosphatase.

Effect of Patient Age The frequency of drug-related abnormalities in

hepatic and hematologic parameters, and serum electrolytes, among approximately 420 azithromycin patients aged 65 years or more, was similar to that in the treated population as a whole. The

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SYhWOSIUM ON TISSUE~DIRECTED ANTIBIOTIC THERAF’Y I HOPKINS

incidence of abnormalities in blood urea nitrogen (1.4%) and creatinine (0.7%) among these elderly patients was slightly higher than among the total population (Table V), but still very low. There were no treatment-related laboratory test abnormalities among approximately 500 azithromycin patients aged 2 to 14 years, including 29 under the age of 5 years.

OTHER TESTS Detailed neurologic and audiometric testing re-

vealed no treatment-related abnormalities during or after treatment with 1.5 g azithromycin over 5 days (37 patients) or a single dose of 1 g (25 patients). Ophthalmologic testing (visual acuity and fields, light and accommodation reflex, slit-lamp, and funduscopy) revealed no evidence of drug- related changes in 42 patients treated with the 5-day regimen. Phospholipidosis, an intracellular phenomenon characterized by ultramicroscopic lamellated structures in the lysosomes of various tissues, was a feature of the high dose animal toxicology of azithromycin. It is associated with a wide variety of drugs (ranitidine, imipramine, aminogly- cosides) and its significance to humans is unknown. Ultramicroscopy revealed no treatment-related myelin figures, which are a sensitive indicator of phospholipidosis, in peripheral blood lymphocytes of eight subjects treated with the 5-day regimen.

ease and medication. Some 30% of azithromycin patients had concurrent disease, commonly essen- tial hypertension, chronic obstructive pulmonary disease, diabetes mellitus, and asthma, and a further 8% developed intercurrent (onset during study) illness, mainly of the respiratory system or general symptoms and ill-defined conditions. As a result, some 45% of azithromycin patients received concomitant medication, commonly bronchodila- tors, analgesics, endocrine corticosteroids, diuret- ics, hypnotics/sedatives/anxiolytics, or antiarthritis drugs. No interaction problems were encountered.

Precautions Azithromycin is contraindicated in patients with

a history of hypersensitivity to this drug or to macrolide antibiotics. In patients receiving ergot alka- loids, azithromycin should not be administered con- currently because related compounds have been reported to precipitate ergotism in such patients.

Since macrolides have been reported to increase the plasma concentrations of digoxin (by altering the gut flora) and cyclosporin and carbamazepine (by inhibition of metabolism), the possibility of en- hanced plasma concentrations of these drugs when coadministered with azithromycin should be borne in mind.

INTERACTIONS AND PRECAUTIONS Interactions

The serum protein binding of azithromycin varies from 7% at 1 pg/ml to 50% at 0.05 pg/ml, and these values are unlikely to influence the protein binding of other drugs or to cause protein binding interactions with other drugs.

Biliary excretion is a major route of elimination of azithromycin, and caution should be exercised when the drug is administered to patients with impaired hepatic function. No dose adjustment is needed in patients with mild renal impairment (creatinine clearance 240 mL/min), but there are no data on azithromycin usage in patients with more severe renal impairment, and caution should be exercised in administering the drug to such patients. No dosage adjustment is needed in the treatment of elderly patients on the grounds of age.

The 5-day (1.5 g) regimen of azithromycin did not affect the prothrombin time response to a single dose of warfarin, or affect the plasma levels or pharmacokinetics of a single intravenous or oral administration of theophylline. There were no pharmacokinetic interactions between azithromycin and carbamazepine or methylprednisolone. Prudent medical practice, however, indicates that the levels of these compounds should be followed closely at all times. Absorption of azithromycin was not affected by the administration of cimetidine (800 mg) 2 hours previously but was reduced by approximately 50% by the presence of food in the stomach. Peak serum levels, but not the total ex- tent of absorption, were reduced by the presence of antacids containing aluminum and magnesium.

Safety data from the clinical studies were obtained in the presence of significant associated dis-

As usual in initial clinical studies, pregnant and lactating women were excluded and consequently there are no data concerning such patients. Repro- duction studies have been performed in rats at doses of up to 60 times the human total dose and revealed no evidence of impaired fertility or harm to the fetus due to azithromycin. There are, however, no adequate well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, azithromyein should be used during pregnancy only if clearly needed. There are no data on secretion into breast milk, and the drug should be administered to nursing moth- ers only if a suitable alternative is not available.

Since there are only limited pharmacokinetic and safety data from children, azithromycin is not indi- cated for the treatment of patients under the age of 16 years at this time.

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SYMPOSIUM ON TISSUE-DIRECTED ANTIBIOTIC THERAPY I HOPKINS

Azithromycin showed no mutagenic potential in standard laboratory tests and no carcinogenicity was evident in routine animal toxicology tests with treatment periods of up to 6 months.

To ensure maximum absorption and optimum therapeutic efficacy, azithromycin should not be coadministered with antacids or within 1 hour before, or 2 hours after, a meal.

In conclusion, azithromycin is well tolerated by adult patients of all ages. As observed in a patient population of 3,995, the overall incidence of side effects is 12%, and less than 10% of these effects are severe. The most common side effects are gastrointestinal in nature (diarrhea 3.6%, abdominal pain 2.5%).

Extensive studies have demonstrated that azithromycin has no major or consistent effect on laboratory safety parameters. Abnormalities occa- sionally appear in the hepatic enzymes, but with a maximum frequency of 1.7% (serum ALT). Al- though prudent medical practice still dictates the monitoring of certain drug levels, no potentially dangerous drug interactions have been identified, and the agent is well tolerated and safe in the presence of a wide variety of concomitant illnesses and medications.

REFERENCE 1. Foulds G, Shepard RM, Johnson RB. The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25 (Suppl A): 73-82.

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Clinical toleration and safety of azithromycin

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