Biaxin
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Biaxin - Scientific Information

Manufacture: Abbott
Country: Canada
Condition: Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bronchitis, Dental Abscess, Helicobacter Pylori Infection, Legionella Pneumonia, Mycoplasma Pneumonia, Mycobacterium avium-intracellulare, Treatment, Mycobacterium avium-intracellulare, Prophylaxis, Nongonococcal Urethritis, Otitis Media, Pertussis, Pertussis Prophylaxis, Pharyngitis, Pneumonia, Sinusitis, Skin and Structure Infection, Skin or Soft Tissue Infection, Strep Throat (Streptococcal Pharyngitis), Toxoplasmosis, Tonsillitis/Pharyngitis, Upper Respiratory Tract Infection
Class: Macrolides
Form: Tablets, Powder, Syrup
Ingredients: clarithromycin, cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, pregelatinized starch (250 mg only), propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, vanillin

Pharmaceutical information

Drug Substance

Proper name:Clarithromycin
Chemical name:(3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-[(2,6-dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl)oxy]-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo-hexopyranosyl]oxy]oxacyclotetradecane-2-10-dione.
Molecular formula:C38H69NO13
Molecular mass: 747.96
Structural formula:



Physicochemical properties:Clarithromycin is a white to off-white crystalline powder. It is slightly soluble in methanol, ethanol and acetonitrile, and practically insoluble in water. The pKa of clarithromycin is 8.48; the pH of a 0.2% (Methanol: Water, 5:95) slurry is 8.8.
The partition coefficient of clarithromycin is influenced by the pH of the water phase and polarity of the organic phase. For octanol (dipole moment = 0.25): water, the partition co-efficient varies from 5.63 to 46.0 for pH water increases from 2 to 8. The melting point of clarithromycin is approximately 225°C.

Clinical Trials

Mycobacterial Infections

Prophylaxis

Table 1 Summary of Demographics and Trial Design Prophylaxis Against M. avium Complex
Study # Trial design Dosage, route of
administration and
duration
Study subjects
Immunocompromised
patients with CD4 counts
<100 cells/μL
Mean age
(Range)
561 Double-blind clarithromycin 500 mg b.i.d (≈10.6 months) 341 Adult
Placebo b.i.d (8.2 months) 341

Legend: b.i.d. = twice daily.

More patients in the placebo arm than the clarithromycin arm discontinued prematurely from the study (75.6% and 67.4%, respectively). However, if premature discontinuations due to Mycobacterium avium complex (MAC) or death are excluded, approximately equal percentages of patients on each arm (54.8% on clarithromycin and 52.5% on placebo) discontinued study drug early for other reasons.

Table 2 Summary of Efficacy Results in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex
Clarithromycin Placebo Hazard Ratio
(95% CI)
p-value Risk
reduction
MAC bacteremia
# patients developed
MAC
19/333 (5.7%)53/334 (15.9%)0.307 (0.177, 0.533)< 0.001*- 69.3%
Survival
# patients died106/341 (31.1%)136/341 (39.9%)0.710 (0.533, 0.934)0.014*28.2%
Emergence of MAC Signs/Symptoms
# meeting
criterion/total
# meeting
criterion/total
Wt. loss >10%5/333 (2%)23/322 (7%)0.179 (0.067, 0.481)0.001*82.1%
Moderate/severe
pyrexia
2/332 (< 1%)10/329 (3%)0.191 (0.041, 0.883)0.034*80.9%
Moderate/severe night
sweats
1/325 (< 1%)7/327 (2%)0.130 (0.016, 1.081)0.05987.0%
Mod./severe night
sweats or pyrexia
2/325 (< 1%)13/326 (4%)0.140 (0.031, 0.632)0.011*86.0%
Moderate/severe anemia0/319 (0%)0
Grade 3 or 4 LFT3/325 (< 1%)0.739 (0.118, 4.649)0.747
Quality of Life Subscores (time to first decrease of ≥ 10 points)
# meeting
criterion/total
# meeting
criterion/total
Overall health180/317 (57%)184/318 (58%)0.809 (0.645, 1.015)0.068
Physical function210/299 (70%)236/306 (77%)0.781 (0.637, 0.956)0.017*- 21.9%
Role function111/189 (59%)131/211 (62%)0.922 (0.690, 1.233)0.585
Social function187/327 (57%)197/331 (60%)0.823 (0.662, 1.024)0.08
Cognitive function174/336 (52%)170/339 (50%)0.990 (0.790, 1.240)0.929
Pain201/331 (61%)217/336 (65%)0.902 (0.731, 1.113)0.355
Mental Health179/336 (53%)184/338 (54%)0.842 (0.672, 1.055)0.134
Energy/fatigue208/328 (63%)217/335 (65%)0.784 (0.636, 0.966)0.022*- 21.6%
Health distress170/335 (51%)191/335 (57%)0.807 (0.647, 1.007)0.057
Quality of life199/330 (60%)199/333 (60%)0.902 (0.727, 1.120)0.352
Hospitalization
# patients
hospitalized
166/339 (49%)189/330 (57%)0.764 (0.610, 0.955)0.018*- 23.6%

On an intent-to-treat basis, the 1-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to clarithromycin and 19.4% for patients randomized to placebo (Table 3). While only 19 of the 341 patients randomized to clarithromycin developed MAC, 11 of these cases were resistant to clarithromycin. The patients with resistant MAC bacteremia had a median baseline CD4 count of 10 cells/mm3 (range 2 to 25 cells/mm3). Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited. The 8 patients who received clarithromycin and developed susceptible MAC bacteremia had a median baseline CD4 count of 25 cells/mm3 (range 10 to 80 cells/mm3). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to clarithromycin. The median baseline CD4 count was 15 cells/mm3 for placebo patients that developed MAC.



Figure 1: Survival of All Randomized Immunocompromized Adult Patients Receiving Clarithromycin in Prophylaxis Against M. avium Complex or Placebo.

Table 3 Cumulative Incidence of MAC Bacteremia and Mortality in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex
Cumulative Incidence of MAC Bacteremia* Cumulative Mortality
Clarithromycin Placebo Clarithromycin Placebo
6 month 1.0 % 9.5 % 6.4 % 9.3 %
12 month 5.0 % 19.4 % 20.8 % 29.7 %
18 month 10.1 % 26.8 % 36.8 % 46.8 %

* from Kaplan-Meier estimates.

Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated.

Treatment of Mycobacterial Infections

Three studies summarized in Table 4 were designed to evaluate the following end points:

  • Change in MAC bacteremia or blood cultures negative for M. avium.
  • Change in clinical signs and symptoms of MAC infection including one or more of the following: fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly.
Table 4 Summary of Demographics and Trial Design Efficacy of Clarithromycin in the Treatment of Mycobacterial Infections
Study # Trial design Dosage, route of administration
and duration
Study subjects (n=number) Mean age
(Range)
500 Randomized,
double-blind
500 mg b.i.d
1000 mg b.i.d
2000 mg b.i.d.
CDC-defined AIDS and
CD4 counts < 100 cells/μL
(n=154)
Adult
577 Open -label* 500 mg b.i.d
1000 mg b.i.d
CDC-defined AIDS and
CD4 counts < 100 cells/μL
(n=469)
Adult
521 Pediatric Study 3.75 mg/kg b.i.d.
7.5 mg/kg b.i.d.
15 mg/kg b.i.d.
CDC-defined AIDS and
CD4 counts < 100 cells/μL
(n=25)
1-20 mo

* compassionate use.

Legend: b.i.d. = twice daily.

The results of the Study 500 are described below. The Study 577 results were similar to the results of the Study 500. Results with the 7.5 mg/kg twice daily dose in the pediatric study were comparable to those for the 500 mg twice daily regimen in the adult studies.

MAC Bacteremia

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose groups. Mean reductions in colony forming units (CFU) are shown below. Included in the table are results from a separate study with a 4-drug regimen (ciprofloxacin, ethambutol, rifampicin, and clofazimine). Since patient populations and study procedures may vary between these 2 studies, comparisons between the clarithromycin results and the combination therapy results should be interpreted cautiously (Table 5).

Table 5 Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy)
500 mg b.i.d. 1000 mg b.i.d. 2000 mg b.i.d. Four Drug
Regimen
(N=35) (N=32) (N=26) (N=24)
1.5 2.3 2.3 1.4

Legend: b.i.d. = twice daily.

Although the 1000 mg and 2000 mg twice daily doses showed significantly better control of bacteremia during the first 4 weeks during therapy, no significant differences were seen beyond that point. The percent of patients whose blood was sterilized as shown by 1 or more negative cultures at any time during acute therapy was 61% (30/49) for the 500 mg twice daily group and 59% (29/49) and 52% (25/28) for the 1000 and 2000 mg twice daily groups, respectively. The percent of patients who had 2 or more negative cultures during acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg twice daily groups and 8% (4/48) for the 2000 mg twice daily group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49), and 13% (6/48) of patients had relapsed in the 500, 1000, and 2000 mg twice daily dose groups, respectively. All of the isolates had a minimum inhibitory concentration (MIC) < 8 mcg/mL at pretreatment. Relapse was almost always accompanied by an increase in MIC. The median time to first negative culture was 54, 41, and 29 days for the 500, 1000, and 2000 mg twice daily groups, respectively.

Clinically Significant Disseminated MAC Disease

Among patients experiencing night sweats prior to therapy, 84% showed resolution or improvement at some point during the 12 weeks of clarithromycin at 500 to 2000 mg twice daily doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given in Table 6.

Table 6 Response Rates for Clinical Signs of MAC
Resolution of Fever Resolution of Night Sweats
b.i.d. dose
(mg)
% ever
afebrile
% afebrile
≥ 6 weeks
b.i.d. dose
(mg)
% ever
resolving
% resolving
≥ 6 weeks
500 67 23 500 85 42
1000 67 12 1000 70 33
2000 62 22 2000 72 36
Weight Gain > 3% Hemoglobin Increase > 1 g
b.i.d. dose
(mg)
% ever
gaining
% gaining
≥ 6 weeks
b.i.d. dose
(mg)
% ever
increasing
%increasing
≥ 6 weeks
500 33 14 500 58 26
1000 26 17 1000 37 6
2000 26 12 2000 62 18

Legend: b.i.d. = twice daily.

The median duration of response, defined as improvement of resolution of clinical signs and symptoms, was 2 to 6 weeks.

Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25 to 33% of patients who continued to show clinical response after 12 weeks.

Survival

Median survival time from study entry (Study 500) was 249 days at the 500 mg twice daily dose compared to 215 days with the 1000 mg twice daily dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg twice daily group versus 13 deaths in 51 patients in the 1000 mg twice daily group. The reason for this apparent mortality difference is not known. Survival in the 2 groups was similar beyond 12 weeks. The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies.

Median survival time from study entry in Study 577 was 199 days for the 500 mg twice daily dose and 179 days for the 1000 mg twice daily dose. During the first 4 weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg twice daily and 18 deaths in 214 patients taking 1000 mg twice daily.

Otitis Media

In a controlled clinical study (317) of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral cephalosporin. In a small number of patients, microbiologic determinations were made at the pre-treatment visit. Table 8 summarizes the presumptive bacterial eradications/clinical cure outcomes (i.e., clinical success). A summary of the study demographics and trial design is presented below.

Table 7 Summary of Demographics and Trial Design U.S. Acute Otitis Media Study Clarithromycin versus Oral Cephalosporin
Study
#
Trial design Dosage, route of administration and
duration
Study subjects
(n=number)
Mean age
(Range)
317Phase III, single-blind (investigator-blind), randomized, multicenterclarithromycin suspension
7.5 mg/ kg/ dose (max 500 mg) b.i.d.
cefaclor suspension
20 mg/kg (max 100 mg q.d.) b.i.d.
379 patientsclarithromycin:
3.8 (0 to 13 years) cefaclor:
4.0 (0 to 12 years)
oral
10 days
497Phase III, single-blind (investigator-blind), randomized, multicenterclarithromycin suspension
7.5 mg/ kg/ dose (max 500 mg) b.i.d.
Augmentin suspension
13.3 mg/ kg/ dose of the amoxycillin component (max 500 mg) q8h
433clarithromycin:
3.5 (0 to 12 years)
Augmentin:
3.3 (0 to 12 years)
oral
10 days
649Phase III, single-blind (investigator-blind), randomized, multicenterclarithromycin suspension
7.5 mg/ kg/ dose (max 500 mg) b.i.d.
Augmentin suspension
13.3 mg/ kg/ dose of the amoxycillin component (max 500 mg)
312Clarithromycin: 3.1 (6 months to 12 years)
Augmentin: 3.5 (6 months to 12 years)
oral
10 days

Legend: b.i.d. = twice daily; q8h = every 8 hours; q.d. = once daily

Table 8 U.S. Acute Otitis Media Study Clarithromycin versus Oral Cephalosporin
Pathogen Efficacy Results
Outcome
S. pneumoniae clarithromycin success rate, 13/15 (87%), control 4/5
H. influenzae* clarithromycin success rate, 10/14 (71%), control 3/4
M. catarrhalis clarithromycin success rate, 4/5, control 1/1
S. pyogenes clarithromycin success rate, 3/3, control 0/1
Overall clarithromycin success rate, 30/37 (81%), control 8/11 (73%)

* None of the H. influenzae isolated pre-treatment were resistant to clarithromycin; 6% were resistant to the control agent.

The incidence of adverse events in all patients treated, primarily diarrhea (15% vs. 38%) and diaper rash (3% vs. 11%) in young children, was clinically or statistically lower in the clarithromycin arm versus the control arm.

In 2 other controlled clinical trials of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor.

For the patients who had microbiologic determinations at the pre-treatment visit, Table 9 summarizes the presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success).

Table 9 Two U.S. Acute Otitis Media Studies Clarithromycin versus Antimicrobial/Beta-Lactamase Inhibitor
Pathogen Efficacy Results
Outcome
S. pneumoniae clarithromycin success rate, 43/51 (84%), control 55/56 (98%)
H. influenzae* clarithromycin success rate, 36/45 (80%), control 31/33 (94%)
M. catarrhalis clarithromycin success rate, 9/10 (90%), control 6/6
S. pyogenes clarithromycin success rate, 3/3, control 5/5
Overall clarithromycin success rate, 91/109 (83%), control 97/100 (97%)

* Of the H. influenzae isolated pre-treatment, 3% were resistant to clarithromycin and 10% were resistant to the control agent.

The incidence of adverse events in all patients treated, primarily diarrhea and vomiting, did not differ clinically or statistically for the 2 agents.

Appropriate culture and susceptibility tests should be performed prior to initiating treatment in order to isolate and identify organisms causing the infection and to determine their susceptibilities to clarithromycin. Therapy with clarithromycin may be initiated before results of these tests are known. However, modification of this treatment may be required once results become available or if there is no clinical improvement.

Eradication of Helicobacter pylori

Triple Therapy: BIAXIN BID/omeprazole/amoxicillin

In a well controlled double-blind study, Helicobacter pylori (H. pylori) infected duodenal ulcer patients received triple therapy with clarithromycin 500 mg twice daily, omeprazole 20 mg daily and amoxicillin 1000 mg twice daily for 10 days or dual therapy with clarithromycin 500 mg three times daily and omeprazole 40 mg daily for 14 days. H. pylori was eradicated in 90% of the patients receiving clarithromycin triple therapy and in 60% of the patients receiving dual therapy.

A summary of the Trial Design is presented in Table 10.

Table 10 Summary of the Trial Design Efficacy of Clarithromycin in the Eradication of Helicobacter pylori - Triple Therapy
Study # Trial design Dosage, route of administration and
duration
Study subjects
(n=number)
Mean age
(Range)
183Phase III, randomized, double-blind, multicenterTreatment 1
Clarithromycin 500 mg b.i.d. with Omeprazole 20 mg q.d. and
Amoxicillin 1000 mg b.i.d.
267 patients18 to 75 years
Treatment 2
Clarithromycin 500 mg b.i.d. with Omeprazole 40 mg q.d.
oral
Treatment 1: 10 days
Treatment 2: 14 days

Legend: b.i.d. = twice daily; q.d. = once daily

The ulcer healing rates and corresponding 95% confidence intervals are presented in Table 11.

Table 11 Ulcer Healing [95% C.I.] at 4- to 6-Week Follow-up
Patient Subset Clarithromycin +
Omeprazole + Amoxicillin
Clarithromycin +
Omeprazole
p-value
Clinically Evaluable 93% (118/127)
[87.0, 96.7]
91% (104/114)
[84.5, 95.7]
0.641
Intent-to-Treat #1 93% (122/131)
[87.4, 96.8]
92% (111/121)
[85.3, 96.0]
0.812
Intent-to-Treat #2 90% (122/136)
[83.3, 94.3]
85% (111/130)
[78.1, 91.0]
0.353

• An ulcer was defined as a circumscribed break in the duodenal mucosa that measured 5 to 25 mm in the longest diameter with apparent depth and was covered with an exudate.

• Duodenal ulcer was identified by endoscopy and H. pylori infection at baseline was defined as at least two of three positive tests from 13C UBT, CLOtest, histology and culture.

• H. pylori eradication at 4 to 6 weeks posttreatment was defined as at least two of three negative tests from 13C UBT gastric biopsy for culture, histology and CLOtest.

Intent-to-Treat #1: excluded patients with no confirmed evidence of H. pylori pretreatment, patients who had no duodenal ulcer pretreatment, and patients who did not return for a particular visit or did not have a particular procedure performed (e.g., endoscopy).

Intent-to-Treat #2: excluded patients with no confirmed evidence of H. pylori pretreatment and patients with no duodenal ulcer pretreatment, but included as failures patients who did not return for a particular visit or did not have a particular procedure performed (e.g., endoscopy).

The H. pylori eradication rates and corresponding 95% confidence intervals are summarized in Table 12.

For all patient subsets, triple therapy with clarithromycin, omeprazole, and amoxicillin achieved a statistically higher eradication rate than dual therapy (p < 0.001). These differences were also observed when the eradication rates were adjusted for potentially influential factors such as ulcer characteristics, age, and smoking. In addition, the eradication rates within each treatment group were similar for smokers and non-smokers.

Table 12 Global Eradication [95% C.I.] at 4- to 6-Week Follow-up
Clarithromycin +
Omeprazole + Amoxicillin
Clarithromycin +
Omeprazole
p-value
Bacteriologically
Evaluable
91% (115/127)
[84.1, 95.0]
59% (68/115)
[49.6, 68.2]
< 0.001
Intent-to-Treat #1 90% (120/133)
[83.9, 94.7]
60% (72/120)
[50.7, 68.8]
< 0.001
Intent-to-Treat #2 88% (120/136)
[81.6, 93.1]
55% (72/130)
[46.4, 64.1]
< 0.001

• An ulcer was defined as a circumscribed break in the duodenal mucosa that measured 5 to 25 mm in the longest diameter with apparent depth and was covered with an exudate.

• Duodenal ulcer was identified by endoscopy and H. pylori infection at baseline was defined as at least two of three positive tests from 13C UBT, CLOtest, histology and culture.

• H. pylori eradication at 4 to 6 weeks posttreatment was defined as at least two of three negative tests from 13C UBT gastric biopsy for culture, histology and CLOtest.

Intent-to-Treat #1: excluded patients with no confirmed evidence of H. pylori pretreatment, patients who had no duodenal ulcer pretreatment, and patients who did not return for a particular visit or did not have a particular procedure performed (e.g., endoscopy).

Intent-to-Treat #2: excluded patients with no confirmed evidence of H. pylori pretreatment and patients with no duodenal ulcer pretreatment, but included as failures patients who did not return for a particular visit or did not have a particular procedure performed (e.g., endoscopy).

International, Randomized, Double-Blind, Placebo-Controlled Study

In an international, randomized, double-blind, placebo-controlled study involving more than 100 patients in each of 6 treatment groups, patients with proven duodenal ulcer disease were randomized to treatment twice daily for 1 week with omeprazole, 20 mg (O), plus either placebo (P) or combinations of 2 of the following antimicrobials: amoxicillin, 1g (A), clarithromycin, 250 mg or 500 mg (C250, C500), or metronidazole, 400 mg (M). H. pylori eradication rates for the “all-patients-treated” analysis were 96% (OAC500), 95% (OMC250), 90% (OMC500), 84% (OAC250), 79% (OAM), and 1% (OP).

Independent, Open and Non-Randomized Study

In an independent, open, and non-randomized study, H. pylori infected patients received eradication therapy with clarithromycin 500 mg twice daily in conjunction with amoxicillin 1000 mg twice daily and omeprazole 20 mg once daily (Group A) or omeprazole 20 mg twice daily (Group B) for 7 days. In those patients not previously treated with anti-H. pylori therapy, H. pylori was eradicated in 88% of patients in Group A and 86% of patients in Group B.

(For additional information on the use of BIAXIN BID in triple therapy for the treatment of H. pylori infection and active duodenal ulcer recurrence, refer to the Hp-PAC Product Monograph).

Pneumonia

BIAXIN XL (clarithromycin extended-release tablets)

The clinical and the bacteriological cure rates for all Clinically and Bacteriologically Evaluable Subjects treated with clarithromycin extended-release (ER) in the Community-Acquired Pneumonia (CAP) pivotal study were 87% and 86%, respectively.

Clinical and bacteriological cure rates with the corresponding confidence intervals for Clinically and Bacteriologically Evaluable Subjects in 2 Studies are presented in Table 14.

A summary of the study demographics and trial design is presented below.

Table 13 Summary of Demographics and Trial Design
Study # Trial design Dosage, route of administration
and duration
Study
subjects
(n=number)
Mean age (Range)
Pivotal Study:
M99-077
Phase III, double-blind, randomized, parallel-group, multicenterclarithromycin ER tablets 2 x 500 mg q.d.

levofloxacin tablets 2 x 250 mg q.d.
299clarithromycin:
49 (19 to 89 years)

levofloxacin:
51.2 (18 to 91 years)
oral
7 days
Non-Pivotal
Study:
M98-927
Phase III, double-blind, randomized, parallel-group, multicenterclarithromycin IR tablets 1 x 250 mg b.i.d. / clarithromycin ER tablets 2 x 500 mg q.d.

trovafloxacin mesylate tablets (placed in capsules) 1 x 200 mg q.d.
176clarithromycin ER:
47.6 (19 to 81 years)
clarithromycin IR:
49.1 (18 to 76 years)

trovafloxacin :
47.3 (19 to 80 years)
oral
7 days

Legend: ER = extended-release; q.d. = once daily

Table 14 Clinical Cure Rates and Bacteriological Cure Rate at the Test-of-Cure Visit*
Pivotal Study Non Pivotal Study
Clarithromycin ER
n/N (%)
[95% CI]a
Clarithromycin ER
n/N (%)
[95% CI]a
Clinical Cure Rateb 81/93 (87%)
[78.5, 93.2]
52/58 (90%)
[78.8, 96.1]
P-valuec; [95% CI]d > 0.999, [-10.0, 8.9] 0.292, [-15.8, 3.6]
Bacteriological Cure
Rateb
80/93 (86%)
[77.3, 92.3]
52/58 (90%)
[78.8, 96.1]
P-valuec; [95% CI]d 0.831, [-11.2, 8.0]e 0.728, [-14.5, 6.5]f

a Exact binomial confidence interval.

b Assessment was made after 7 days posttreatment in pivotal study and between 7-28 days posttreatment in non-pivotal study unless the subject was a prior clinical failure.

c P-value is from Fisher's exact test comparing treatment groups.

d Binomial confidence interval based on normal approximation.

e comparator is levofloxacin.

f comparator is trovafloxacin mesylate.

* Clinically and Bacteriologically Evaluable Subjects in the CAP Studies.

Legend: ER = extended-release.

Acute Bacterial Exacerbation of Chronic Bronchitis

BIAXIN XL (clarithromycin extended-release tablets)

5-Day Treatment Regimen

One double-blind, controlled study was conducted to evaluate efficacy and safety of clarithromycin extended-release 1000 mg once daily for 5 days treatment of ABECB, as presented in Table 15.

Table 15 Summary of Demographics and Trial Design Efficacy of Clarithromycin ER in Acute Bacterial Exacerbation of Chronic Bronchitis – 5-day treatment
Study # Trial design Dosage, route of administration
and duration
Study subjects
(n=number)
Mean age
(Range)
472 Phase III,
Double-blind,
randomized,
parallel-group,
multicenter
Clarithromycin ER
2 x 500 mg q.d for 5 days

Clarithromycin IR
500 mg b.i.d for 7 days

Oral
Patients with ABECB
(n = 485)
Clarithromycin ER
62.1 (18-93)

Clarithromycin IR
61.6 (34-88)

Legend: b.i.d. = twice daily; q.d. = once daily; ER = extended-release; IR = immediate-release

The bacteriological cure rate for all Clinically and Bacteriologically Evaluable Subjects treated with clarithromycin extended-release in the Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) pivotal study was 87%.

Bacteriological cure rates with the corresponding confidence intervals for Clinically and Bacteriologically Evaluable Subjects are presented in Table 16.

Table 16 Bacteriological Cure Rates at the Test-of-Cure Visit*
Clarithromycin ER
n/N (%)
Clarithromycin IR
n/N (%)
Bacteriological Cure Rateb 82/94 (87%) 91/102 (89%)
95% CIa [78.8, 93.2] [81.5, 94.5]
Comparison of Cure Rates
P-valuec p = 0.825
95% CI for Difference in Cure Rate d [-11.6, 7.6]

a Exact binomial confidence interval.

b Bacteriological assessment was made at Evaluation 4 (between Study Days 14 and 40), unless the subject was a bacteriological failure.

c P-value is from Fisher's exact test comparing treatment groups.

d Binomial confidence interval based on normal distribution approximation with a continuity correction.

* Clinically and Bacteriologically Evaluable Subjects in the ABECB Study.

Legend: ER = extended-release; IR = immediate-release.

The clinical cure rates for all Clinically and Bacteriologically Evaluable Subjects treated with clarithromycin extended-release in the Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) pivotal study are presented in Table 17.

Table 17 Clinical Cure Rates for Target Pathogens
Pretreatment Target Pathogen Clarithromycin ER Clarithromycin IR p-valuea
H. influenzae 34/40 (85%) 34/38 (89%) 0.738
H. parainfluenzae 23/28 (82%) 39/43 (91%) 0.304
M. catarrhalis 24/26 (92%) 14/18 (78%) 0.208
S. pneumoniae 14/19 (74%) 15/20 (75%) > 0.999
S. aureus 7/9 (78%) 10/12 (83%) > 0.999

a p-value from Fisher’s exact test comparing treatment groups.

Legend: ER = extended-release; IR = immediate-release.

Long-term (3 months) recurrence rates of ABECB after 5-day treatment with clarithromycin extended-release has not been investigated in the pivotal trial.

7-Day Treatment Regimen

One double-blind controlled clinical trial was conducted to evaluate the efficacy and safety of clarithromycin 500 mg two tablets once daily for 7 days treatment of ABECB, as presented in Table 18.

Table 18 Summary of Demographics and Trial Design Efficacy of Clarithromycin ER in Acute Bacterial Exacerbation of Chronic Bronchitis - 7days treatment
Study # Trial design Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
756 Phase III,
Double-blind,
randomized,
parallel-group,
multicenter.
Clarithromycin ER
2 x 500 mg q.d for 7 days

Clarithromycin IR
500 mg b.i.d for 7 days
Patients with
ABECB
(n = 627)
54.4 years
(14 to 89)

Legend: b.i.d. = twice daily; q.d. = once daily; ER = extended-release; IR = immediate-release.

The primary efficacy parameters evaluated in Study 756 were the bacteriological cure rates, target pathogen eradication and clinical cure rates. Bacteriological and clinical cure rates with the corresponding confidence intervals for Clinically and Bacteriologically Evaluable Subjects are presented in Table 19.

Table 19 Bacteriological and Clinical Cure Rates at Test-of-Cure Visit - Study 756
Clarithromycin ER
n/N (%)
[95% CI]b
Clarithromycin IR
n/N (%)
[95% CI]b
P-valuea
[95% CI]c
Bacteriological Cure Rated 85/99*(86%)
[77.4, 92.0]
70/82 (85%)
[75.8, 92.2]
> 0.999
[-9.8, 10.8]
Clinical Cure Rate 83/100 (83 %)
[74.2, 89.8]
67/82 (82%)
[71.6, 89.4]
0.847
[-9.9, 12.4]

* One subject with indeterminate bacteriological response was not included in calculating the rate.

a P-value is from Fisher’s exact test comparing treatment groups.

b Exact binomial confidence interval.

c Binomial confidence interval based on normal approximation.

d Assessment was made at Evaluation 3 (7 to 23 days post-treatment) unless the subject was a bacteriological failure before Evaluation 3.

Legend: ER = extended-release; IR = immediate-release.

Overall eradication rates and corresponding confidence intervals, as well as target pathogen eradication rates, for clinically and bacteriologically evaluabale subjects are presented in Table 20.

Table 20 Target Pathogen Eradication Rates at Test-of-Cure Visit - Study 756
Clarithromycin ER
n/N (%)
[95% CI]b
Clarithromycin IR
n/N (%)
[95% CI]b
P-valuea
[95% CI]c
Overall Pathogen Eradication
Rated
100/116 (86 %)
[78.6, 91.9]
86/98 (88%)
[79.6, 93.5]
0.840
[-10.6, 7.5]
Eradication Rated
H. infuenzae 22/28 (79%) 17/22 (77%) 0.840
[-10.6, 7.5]
M. catarrhalis 22/25* (88%) 25/26* (96%)
S. pneumoniae 22/25 (88%) 9/11 (82%)
H. parainfluenzae 24/26 (92%) 25/28 (89%)
S. aureus 10/12 (83%) 10/11 (91%)

* One subject with indeterminate bacteriological response was not included in calculating the rate.

a P-value is from Fisher’s exact test comparing treatment groups.

b Exact binomial confidence interval.

c Binomial confidence interval based on normal approximation.

d Assessment was made at Evaluation 3 (7 to 23 days post-treatment) unless the subject was a bacteriological failure before Evaluation 3.

Comparative Bioavailability Studies

Relative Bioavailability of Clarithromycin Film-Coated Tablet (Reformulated) and Clarithromycin Film-Coated Tablet Formulations

A re-formulated 500 mg BIAXIN BID has been developed. The new ovaloid, smooth, film-sealed tablet is slightly smaller than the original formulation. The results of the bioequivalence study comparing the two BIAXIN BID formulations may be found in Table 22, and the effect of food on the new tablet may be found in Table 23. A summary of the study demographics and trial design is presented in Table 21.

Table 21 Summary of Demographics and Trial Design
Study # Trial design Dosage, route of administration and
duration
Study subjects
(n=number)
enrolled
Mean age
(Range)
747 Phase I, Single-dose,
open-label, randomized,
four-period complete
crossover in fasting and
non-fasting healthy
subjects
500 mg clarithromycin tablets ( test formulation) single dose 500 mg clarithromycin tablets (reference formulation) single dose 56* 34.6
(19 to 49)
oral
single dose in each of the 4 periods.

* 54 subjects completed the study.

Table 22 Comparative Single-Dose Bioavailability Data for Clarithromycin – BIAXIN BID 500 mg (New Formulation) versus BIAXIN BID 500 mg (Original Formulation) under Fasting Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
BIAXIN BID Test
500 mg film-coated tablet
(New Formulation)
BIAXIN BID Reference
500 mg film-coated tablet
(Original Formulation)
Point
Estimate
(%)+
90%
Confidence
Interval
AUCT (mcg∙h/mL) 16.3 (30) 16.9 (36) 99.5 92.5 – 107.1
AUC (mcg∙h/mL) 17.8 (38) 17.6 (34) 101.7 94.2 – 109.8
Cmax (mcg/mL) 2.38 (36) 2.39 (41) 103.2 93.0 – 114.5
Tmax (hr) 1.9 (41) 2.4 (90) - -
t1/2 (hr) 5.9 (150) 5.0 (33) - -

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Table 23 Effect of Food Data for Clarithromycin – BIAXIN BID 500 mg (New Formulation) Non-Fasting (High-Fat Meal) versus Fasting Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
BIAXIN BID
500 mg film-coated tablet
(New Formulation) High-
Fat Meal
BIAXIN BID
500 mg film-coated tablet
(New Formulation)
Fasting
Point
Estimate
(%)+
90%
Confidence
Interval
AUCT (mcg∙h/mL) 16.8 (36) 16.3 (30) 100.1 91.7 – 109.2
AUC (mcg∙h/mL) 17.3 (36) 17.8 (38) 95.8 87.4 – 104.9
Cmax (mcg/mL) 2.98 (38) 2.38 (36) 123.6 109.3 – 139.9
Tmax (hr) 2.5 (40) 1.9 (41) - -
t1/2 (hr) 4.4 (18) 5.9 (150) - -

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Because the 90% confidence intervals (90% CIs) for Cmax and AUC in Table 22 are within the range of 80 to 125%, the new and original tablet formulations are bioequivalent under fasting conditions.

When administered under non-fasting (high-fat meal) conditions, the Cmax for the new tablet is slightly higher than when it is administered under fasting conditions and the upper limit of the 90% CI (139.9%) is greater than 125%. However, the AUC values under fasting and non-fasting conditions are bioequivalent (90% CIs for AUC in Table 23 are within the range 80 to 125%). As with the original tablet formulation, the new BIAXIN BID tablet may be taken without regard to meals.

BIAXIN XL (clarithromycin extended-release tablets)

Relative Bioavailability of Clarithromycin Extended-Release Tablet and Clarithromycin Film-Coated Tablet Formulations

Steady-state pharmacokinetic studies compared the new clarithromycin extended-release 500 mg tablet dosage form to the standard 250 mg and 500 mg clarithromycin immediate-release film-coated tablets.

In the first study, the steady-state pharmacokinetics of clarithromycin and 14-OH-clarithromycin were studied in 30 healthy subjects under non-fasting (moderate-fat meal) conditions. The subjects received clarithromycin extended-release tablets (2 x 500 mg once daily) or clarithromycin immediate-release film-coated tablets (500 mg twice daily). The pharmacokinetic and bioavailability parameters for clarithromycin are summarized in Table 24.

Table 24 Comparative Steady-State Bioavailability Data for Clarithromycin – Three Lots of BIAXIN XL 500 mg (ER Tablets) versus BIAXIN BID 500 mg (IR Tablets) under Non-Fasting (Moderate-Fat Meal) Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
ER Tablet
Regimen A
ER Tablet
Regimen B
ER Tablet
Regimen C
IR Tablet
Regimen D
Point
Estimate (%)+
Confidence
Interval*
AUCτ (mcg∙h/mL)42.2 (30)44.9 (34)42.1 (31)46.1 (30)A vs. D: 92.1
B vs. D: 96.2
C vs. D: 90.3
85.4 – 99.4
89.1 – 103.8
83.7 – 97.5
Cmax (mcg/mL)2.81 (37)2.78 (34)2.59 (27)3.51 (28)A vs. D: 79.2
B vs. D: 77.2
C vs. D: 72.9
71.8 – 87.3
70.0 – 85.1
66.1 – 80.4
Cmin (mcg/mL)0.83 (41)0.83 (53)0.76 (49)0.91 (43)A vs. D: 94.3
B vs. D: 86.0
C vs. D: 79.0
75.9 – 117.3
69.1 – 106.9
63.5 – 98.2
Tmax (hr)6.5 (61)5.5 (63)7.8 (51)2.1 (28)--
FI (%)113 (26)107 (27)108 (26)138 (18)--

Regimen A = 2 x 500 mg clarithromycin ER tablet lot 1, every morning for 5 days.

Regimen B = 2 x 500 mg clarithromycin ER tablet lot 2, every morning for 5 days.

Regimen C = 2 x 500 mg clarithromycin ER tablet lot 3, every morning for 5 days.

Regimen D = 1 x 500 mg clarithromycin immediate-release film-coated (IR) tablet, every 12 hours for 5 days.

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

* 90% confidence intervals for AUCτ; 95% confidence intervals for Cmax and Cmin.

Legend: ER = extended-release; FI = Fluctuation Index; IR = immediate release.

The results from this multiple-dose study showed that at steady-state under non-fasting conditions, all 3 lots of the test extended-release formulation met the requirements for demonstrating bioavailability with respect to AUCτ. The significantly lower clarithromycin Cmax values and the longer Tmax values suggested that the test formulation provided extended release of clarithromycin in vivo. The significantly lower fluctuation index (FI) values indicated that clarithromycin plasma concentrations fluctuated less for the extended-release tablet regimens than for the immediate-release tablet regimen.

In the second study, the steady-state pharmacokinetics of clarithromycin and 14-OH-clarithromycin were studied in 32 healthy subjects under non-fasting (moderate-fat meal) conditions. The subjects received a clarithromycin extended-release 500 mg tablet once daily or clarithromycin 250 mg immediate-release film-coated tablet twice daily.

The pharmacokinetic and bioavailability parameters for clarithromycin are summarized in Table 25.

Table 25 Comparative Steady-State Bioavailability Data for Clarithromycin – BIAXIN XL 500 mg (ER Tablets) versus BIAXIN BID 250 mg (IR Tablets) under Non-Fasting (Moderate-Fat Meal) Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
ER Tablet
Regimen A
IR Tablet
Regimen B
Point
Estimate
(%)+
Confidence
Interval*
AUCT
(mcg∙h/mL)
20.4 (43) 21.0 (33) 94.6 84.8 – 105.5
Cmax (mcg/mL) 1.45 (30) 1.94 (35) 75.8 67.7 – 84.9
Cmin (mcg/mL) 0.31 (73) 0.34 (45) 75.1 59.2 – 102.8
Tmax (hr) 5.6 (38) 2.4 (59) - -
FI (%) 148 (36) 184 (22) - -

Regimen A = 1 x 500 mg clarithromycin ER tablet, every morning for five days.

Regimen B = 1 x 250 mg clarithromycin immediate-release film-coated (IR) tablet, every 12 hours for five days.

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

* 90% confidence intervals for AUCτ; 95% confidence intervals for Cmax and Cmin.

Legend: ER = extended-release; FI = Fluctuation Index; IR = immediate release.

The results from this multiple-dose study showed that the extended-release tablet was not significantly different from the 250 mg film-coated tablet in terms of AUCτ. The significantly lower clarithromycin Cmax values and longer Tmax values suggested that the test formulation provided extended release of clarithromycin in vivo. The significantly lower FI values indicated that clarithromycin plasma concentrations fluctuated less for the extended-release tablet regimen than for the immediate-release regimen.

In the third study, the steady-state pharmacokinetics of clarithromycin and 14-OH-clarithromycin were studied in 32 healthy subjects. The subjects received clarithromycin extended-release tablets (2 x 500 mg) once daily under fasting or non-fasting (high-fat meal) conditions. The pharmacokinetic and bioavailability parameters for clarithromycin are summarized in Table 26.

Table 26 Effect of Food on the Steady-State Bioavailability of Clarithromycin – BIAXIN XL 500 mg (ER Tablets) – Fasting versus Non-Fasting (High-Fat Meal) Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
ER Tablet
Fasting
Regimen A
IR Tablet
Non-Fasting
Regimen B
Point
Estimate
(%)+
Confidence
Interval*
AUCτ(mcg∙h/mL) 35.9 (35) 49.2 (21) 70.1 62.4 – 78.7
Cmax (mcg/mL) 2.33 (30) 3.91 (27) 58.7 51.4 – 67.0
Cmin (mcg/mL) 0.76 (58) 0.80 (48) 95.9 72.0 – 125.8
Tmax (hr) 5.5 (57) 5.6 (35) - -
FI (%) 113 (40) 153 (29) - -

Regimen A = 2 x 500 mg clarithromycin ER tablets under fasting conditions, every morning for 5 days.

Regimen B = 2 x 500 mg clarithromycin ER tablets under non-fasting conditions, every morning for 5 days.

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

* 90% confidence intervals for AUCτ; 95% confidence intervals for Cmax and Cmin.

Legend: ER = extended-release; FI = Fluctuation Index.

The results from this multiple-dose study showed that the clarithromycin Cmax and AUCτ central values for the extended-release clarithromycin tablet formulation administered under fasting conditions were approximately 41% and 30% lower, respectively than the central values for the same formulation administered with high-fat meal. The clarithromycin Cmin values were similar when the extended-release formulation was given under fasting versus non-fasting conditions.

BIAXIN (clarithromycin for oral suspension USP)

Relative Bioavailability of Clarithromycin for Oral Suspension and Clarithromycin Tablet Formulations

Plasma concentrations of clarithromycin and 14-OH-clarithromycin were studied in 22 healthy male adult volunteers following administration of single 250 mg oral doses of clarithromycin as granules for suspension or as a 250 mg immediate-release tablet. Each participant received 3 clarithromycin regimens.

Regimen A: 250 mg (10 mL) clarithromycin oral suspension under non-fasting conditions (30 min after the start of breakfast);
Regimen B: 250 mg (10 mL) clarithromycin oral suspension under fasting conditions (2 hours before breakfast after a minimum 12 hour overnight fast);
Regimen C: one 250 mg immediate-release tablet under fasting conditions (2 hours before breakfast after a minimum 12-hour overnight fast).

Mean plasma concentrations of clarithromycin and 14-OH-clarithromycin are illustrated in Figure 2.



Figure 2: Mean Plasma Clarithromycin (A) and 14-OH-Clarithromycin (B) Concentration vs Time Data After Oral Administration of 250 mg of Clarithromycin.

A summary of pharmacokinetic parameters is presented in Table 27.

Table 27 Comparative Single-Dose Bioavailability Data for Clarithromycin – BIAXIN (Clarithromycin for Oral Suspension) versus BIAXIN BID 250 mg (IR Tablet) underFasting Conditions and the Effect of Food on the Bioavailability of BIAXIN (Clarithromycin for Oral Suspension)
Parameter Arithmetic Mean (CV%) Relative Bioavailability
Suspension
Non-Fasting
Regimen A
Suspension
Fasting
Regimen B
Tablet
Fasting
Regimen C
Point
Estimate
(%)+
90% Confidence
Interval
Clarithromycin
AUCτ
(mcg∙h/mL)
6.52 (57) 7.23 (35) 6.33 (36) A vs. B: 90.0
B vs. C: 114.0
77.5 – 102.4
99.8 – 128.2
Cmax
(mcg∙h/mL)
0.95 (47) 1.24 (29) 1.10 (30) A vs. B: 77.8
B vs. C: 112.1
63.8 – 91.8
96.4 – 127.8
Cmin
(mcg/mL)
5.3 (36) 3.3 (35) 1.7 (36) - -
Tmax (hr) 3.7 3.7 3.3 - -
14(R)-Hydroxy-Clarithromycin
AUCτ
(mcg∙h/mL)
4.26 (35) 4.65 (25) 4.92 (29) A vs. B: 91.1
B vs. C: 93.9
78.5 – 103.7
82.1 – 105.7
Cmax
(mcg/mL)
0.38 (30) 0.42 (34) 0.55 (32) A vs. B: 90.4
B vs. C: 76.1
77.3 – 103.5
66.1 – 86.0
Tmax (hr) 5.8 (27) 3.4 (36) 1.9 (30) - -
t1/2 (hr) 6.7 7.9 6.9 - -

Regimen A = 250 mg (10 mL) clarithromycin oral suspension under non-fasting conditions (30 min after the start of breakfast).

Regimen B = 250 mg (10 mL) clarithromycin oral suspension under fasting conditions (2 hours before breakfast after a minimum 12-hour overnight fast).

Regimen C = 250 mg clarithromycin IR tablet under non-fasting conditions (30 min after the start of breakfast).

* Harmonic mean half-life.

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Legend: IR = immediate-release.

The relative bioavailability of the oral suspension formulation compared with the tablet can be seen by comparing Regimen B versus Regimen C. The difference in clarithromycin Tmax (3.30 ± 1.20 vs.1.70 ± 0.60 hr) with the oral suspension and tablet formulations, respectively, shows that the onset and/or rate of absorption from the suspension is slower. A similar trend is seen with the 14-OH metabolite. For clarithromycin, Cmax was not significantly different between the formulations but for the 14-OH metabolite, Cmax after suspension administration was significantly lower than after tablet administration. The extent of absorption of clarithromycin was not significantly different from that of the tablet as assessed by AUC, whereas for the 14-OH metabolite, the tablet formulation was associated with a significantly higher extent of metabolite formation than the suspension formulation.

The difference between clarithromycin Tmax values under non-fasting and fasting conditions (Regimens A and B) was 5.30 ± 1.90 versus 3.30 ± 1.20 hr, respectively, and was similar for 14-OH-clarithromycin (5.80 ± 1.60 vs. 3.40 ± 1.20 hr). Therefore, the onset and/or rate of absorption from the suspension formulation is slowed by the presence of food.

For clarithromycin, Cmax was significantly higher under fasting than under non-fasting conditions. The extent of absorption of clarithromycin and formation of 14-OH-clarithromycin were not significantly different between fasting and the non-fasting conditions as assessed using AUC.

Single- and multiple-dose adult volunteer studies have established that the suspension and tablet formulations have similar pharmacokinetics.

Relative Bioavailability of Clarithromycin for Oral Suspension (Fruit Punch) and Clarithromycin for Oral Suspension (Fruit-of-the Forest) Formulations

Single-dose adult volunteer studies show that the reformulated (125 mg/5 mL and 250 mg/5 mL, fruit punch flavor) and the previously-marketed (125 mg/5 mL, fruit -of-the-forest flavor) clarithromycin for oral suspension formulations are bioequivalent under both fasting and non-fasting conditions. The results of the bioavailability comparisons are provided in Table 28 and Table 29.

Table 28 Comparative Single-Dose Bioavailability Data for Clarithromycin – Reformulated 125 mg/5 mL Clarithromycin for Oral Suspension (Fruit Punch) versus Reference 125 mg/5 mL Clarithromycin for Oral Suspension (Fruit-of-the-Forest) under Fasting and Non-Fasting Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
Reform.
Fasting
Regimen A
Reference
Fasting
Regimen B
Reform
Non-Fasting
Regimen C
Reference
Non-Fasting
Regimen D
Point
Estimate
(%)+
90%
Confidence
Interval
AUCT
(mcg∙h/mL)
7.95 (35)8.28 (39)7.84 (36)8.37 (37)A vs. B: 97
C vs. D: 93
93 – 102
89 – 99
AUC
(mcg∙h/mL)
8.14 (36)8.46 (39)8.05 (37)8.60 (38)A vs. B: 98
C vs. D: 93
93 – 102
89 – 99
Cmax
(mcg/mL)
1.33 (29)1.35 (39)1.26 (35)1.31 (28)A vs. B: 101
C vs. D: 95
96 – 107
90 – 102
Tmax (hr)3.2 (30)3.3 (30)4.0 (22)4.1 (19)--
t1/2 (hr)3.8 (17)3.8 (15)4.1 (16)4.1 (15)--

Regimen A = 250 mg clarithromycin (10 mL reformulated oral suspension) under fasting conditions.

Regimen B = 250 mg clarithromycin (10 mL reference oral suspension) under fasting conditions.

Regimen C = 250 mg clarithromycin (10 mL reformulated oral suspension) under non-fasting conditions.

Regimen D = 250 mg clarithromycin (10 mL reference oral suspension) under non-fasting conditions.

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Table 29 Comparative Single-Dose Bioavailability Data for Clarithromycin – Reformulated 250 mg/5 mL Clarithromycin for Oral Suspension (Fruit Punch) versus Reference 125 mg/5 mL Clarithromycin for Oral Suspension (Fruit-of-the-Forest) under Fasting and Non-Fasting Conditions
Parameter Arithmetic Mean (CV%) Relative Bioavailability
Reform.
Fasting
Regimen A
Reference
Fasting
Regimen B
Reform
Non-Fasting
Regimen C
Reference
Non-Fasting
Regimen D
Ratio of
Geometric
Means (%)
90%
Confidence
Interval
AUCT
(mcg∙h/mL)
9.87 (32)9.62 (32)9.52 (30)9.57 (32)A vs. B: 103
C vs. D: 100
99 – 108
95 – 105
AUC
(mcg∙h/mL)
10.15 (32)9.88 (33)9.88 (31)9.93 (33)A vs. B: 103
C vs. D: 100
99 – 108
96 – 105
Cmax
(mcg/mL)
1.56 (29)1.53 (27)1.45 (22)1.44 (26)A vs. B: 102
C vs. D: 102
95 – 109
96 – 109
Tmax (hr)3.6 (32)3.4 (28)4.2 (18)4.1 (19)--
t1/2 (hr)4.0 (17)4.0 (16)4.3 (17)4.3 (18)--

Regimen A = 250 mg clarithromycin (5 mL reformulated oral suspension) under fasting conditions.

Regimen B = 250 mg clarithromycin (10 mL reference oral suspension) under fasting conditions.

Regimen C = 250 mg clarithromycin (5 mL reformulated oral suspension) under non-fasting conditions.

Regimen D = 250 mg clarithromycin (10 mL reference oral suspension) under non-fasting conditions.

+ Antilogarithm of the difference (test minus reference) of the least squares means for logarithms.

Detailed Pharmacology

General

Helicobacter pylori

The presence of H. pylori may damage the mucosal integrity and defenses so that exposure to acid/pepsin, even in normal concentrations, produces ulceration.

H. pylori displays potent urease activity which may produce an alkaline environment around the organism. Excess ammonia produced by urea hydrolysis is toxic to mucosal cells and may lead to parietal cell failure and/or to a disturbance of the normal negative feedback of acid to the antral G-cells which secrete gastrin. In addition, H. pylori produces catalases, lipases, phospholipases, proteases, adhesins and toxins. These enzymes may further degrade the mucous layer and damage the epithelial cell membrane. Also, the presence of H. pylori stimulates an active inflammatory response which contributes to mucosal damage.

Gustavson et al. (1995) showed that concentrations of 39.3, 23.1 and 25.2 mcg/g clarithromycin were achieved in the gastric mucosa 2, 4, and 6 hours respectively after administering 500 mg clarithromycin three times daily and that corresponding concentrations of the 14-OH metabolite were 3.2, 1.1, and 4.1 mcg/g respectively. Similar results were obtained whether or not clarithromycin was given alone or together with 40 mg omeprazole once daily (Logan et al., 1995). Although the activity of the 14-OH metabolite is about half of the parent drug and its concentrations are lower, it may still contribute antibacterial activity.

Pharmacokinetics

Pharmacokinetics for clarithromycin and 14-OH-clarithromycin metabolite following the oral administration of a single dose or multiple doses of clarithromycin are outlined below.

Clarithromycin Tablets USP, Film-Coated

Pharmacokinetics for clarithromycin and 14-OH-clarithromycin metabolite was first studied following the oral administration of a single dose of 250 mg or 500 mg or multiple doses of clarithromycin 250 mg tablet.

Single Dose

Plasma levels were determined in 20 subjects following oral administration of a single-dose of 250 mg or 500 mg of clarithromycin under fasting conditions. Cmax occurred at 1.00 and 1.77 (mg/L) and Tmax were 1.5 and 2.2 hours, respectively for the 250 mg and 500 mg (Table 30, Figure 3 and Figure 4).

Table 30 Mean (± SD) Pharmacokinetic Parameters for Clarithromycin Administered as a Single Dose in the Absence of Food
Variable Clarithromycin Dose
250 mg 500 mg
Number of male evaluable patients 20 20
Cmax (mg/L) 1.00 ± 0.34 1.77 ± 0.65
Cmax/100 mg1 0.40 0.35
Tmax (hr) 1.5 ± 0.8 2.2 ± 0.7
AUC (mg.hr/L) 5.47 ± 1.932 11.66 ± 3.673
AUC/100 mg1 2.19 2.33

1 Cmax/100 mg = Cmax x; AUC/100 mg = AUC x

2 AUC0-12 hr

3 AUC0-14 hr



Figure 3: Plasma Clarithromycin Concentration (mg/mL) vs Time Following Oral Administration of a Single Dose of Clarithromyicn 250 mg



Figure 4: Plasma Clarithromycin Concentration (mg/L) vs Time Following Oral Administration of a Single Dose of Clarithromycin 500 mg

Multiple Dose

Representative estimated pharmacokinetic parameters for clarithromycin and 14-OH-clarithromycin metabolite after a single oral 250 mg dose and after the 5th dose of clarithromycin administered orally at 250 mg twice daily are listed in Table 31.

Table 31 Representative Estimated Single and Multiple-Dose Pharmacokinetic Parameters for Clarithromycin and 14-OH-Clarithromycin
Variables Single Dose
(250 mg)
Multiple Dose after 5th Dose
(250 mg b.i.d.)
Clari. 14-OH Clari. 14-OH
Cmax (mg/L) 0.74 ± 0.24 0.61 ± 0.17 1.00 ± 0.29 0.63 ± 0.19
t½ (hr) 2.7 4.2 3.5 4.7
AUC0-12 (mg•h/L) 4.27 ± 1.52 4.91 ± 1.12 6.34 ± 1.82 4.72 ± 1.29

Legend: Clari. = clarithromycin; 14-OH = 14-OH-clarithromycin; b.i.d. = twice daily.

The pharmacokinetics of clarithromycin and its 14-OH metabolite indicate that the steady-state concentration is achieved by the 5th dose using 250 mg of clarithromycin twice daily.

The mean plasma concentration-time along the predicted curves for clarithromycin and 14-OH-clarithromycin metabolite are shown in Figure 5.



Figure 5: Mean Plasma Concentrations of Clarithromycin and 14-OH-Clarithromycin vs Time Following Seven 250 mg B.I.D. Oral Doses of Clarithromycin

At 250 mg twice daily, approximately 20% of an orally administered dose is excreted in the urine as the unchanged parent drug. The urinary excretion of unchanged clarithromycin is somewhat greater (approximately 30%) with 500 mg twice daily dosing. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH-clarithromycin which accounts for an additional 10 to 15% of the dose with twice daily dosing at either 250 mg or 500 mg.

Most of the remainder of the dose is eliminated in the feces, primarily via the bile. About 5 to 10% of the parent drug is recovered from the feces. Fecal metabolites are largely products of N-demethylation, 14-hydroxylation or both.

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH-clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH-clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin were also altered in subjects with impaired renal function. See WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Clarithromycin and Omeprazole

A pharmacokinetic study was conducted with clarithromycin 500 mg three times daily and omeprazole 40 mg once daily. When clarithromycin was given alone at 500 mg every 8 hours, the mean steady-state Cmax value was approximately 31% higher and the mean Cmin value was approximately 119% higher than when clarithromycin is compared with a previous study at 500 mg every 12 hours. The mean AUC0−24 for clarithromycin was 65% greater when 500 mg clarithromycin was given every 8 hours rather than every 12 hours. Neither Tmax nor half-life values appeared substantially different between the every-8-hour and every-12-hour regimens.

When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC0-24 were observed. For all subjects combined, the mean omeprazole AUC0-24 was 89% greater and the harmonic mean for omeprazole t½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady-state Cmax, Cmin, and AUC0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

At steady-state, clarithromycin gastric mucus concentrations 6 hours post dosing were approximately 25-fold higher in the clarithromycin/omeprazole group compared with the clarithromycin alone group. Six hours post-dosing, mean clarithromycin gastric tissue concentrations were approximately 2-fold higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo.

Clarithromycin distributes readily into body tissues and fluids, and provides tissue concentrations that are higher than serum concentrations. Examples from tissue and serum concentrations are presented in Table 32.

Table 32 Representative Clarithromycin Tissue and Serum Concentrations
Tissue Type Concentrations
(after 250 mg b.i.d.)
Tissue (mcg/g) Serum (mcg/mL)
Tonsil 1.6 0.8
Lung 8.8 1.7
Leukocytes* 9.2 1.0

* in vitro data.

Legend: b.i.d. = twice daily

Clarithromycin for Oral Suspension USP

Adults

Plasma concentrations of clarithromycin and 14-OH-clarithromycin were studied in 17 healthy male adult volunteers following the administration of clarithromycin granules for suspension. A single phase dose was followed by the multiple dose phase. During the single dose phase, an oral 250 mg (10 mL) dose of clarithromycin granules for suspension was administered. Doses were administered in a fasting state (2 hours before breakfast after an overnight fast and 2 hours after dinner). Mean plasma concentrations of clarithromycin and 14-OH-clarithromycin are illustrated in Figure 6.



Figure 6: Mean Plasma Clarithromycin (A) and 14-OH-Clarithromycin (B) Concentration of Single and Multiple (Every 12-hours) Dose Administration(s) of 250 mg of Clarithromycin

A summary of pharmacokinetic parameters is presented in Table 33. After a single- and multiple-dose administration of clarithromycin as a suspension formulation, times to attain peak plasma clarithromycin and 14-OH-clarithromycin concentrations were prolonged, as evidenced by mean Tmax values ranging from 2.8 to 3.2 and 2.9 to 3.4 hours, respectively. Steady-state was achieved by Dose 5.

Table 33 Clarithromycin and 14-OH-Clarithromycin Pharmacokinetic Parameters
Parameters Single Dose
Mean ± SD
5th Dose
Mean ± SD
7th Dose
Mean ± SD
Comparison1
1 vs 5 5 vs 7
Clarithromycin
Cmax (mcg/mL)1.34 ± 0.371.98 ± 0.552.15 ± 0.62*NS
Tmax (hr)3.2 ± 1.12.8 ± 0.63.1 ± 0.9--
Cmin (mcg/mL)0.17 ± 0.100.32 ± 0.220.39 ± 0.25**
AUC2 (mcg•hr/mL)7.80 ± 2.8711.5 ± 4.612.7 ± 4.8*NS
t½3 (hr)3.63.23.5--
fu (% of dose)-36.9 ± 11.140.0 ± 14.0-NS
14-OH-Clarithromycin
Cmax (mcg/mL)0.46 ± 0.160.67 ± 0.150.72 ± 0.16*NS
Tmax (hr)3.4 ± 1.22.9 ± 1.03.0 ± 1.0--
Cmin (mcg/mL)0.14 ± 0.040.23 ± 0.070.27 ± 0.07**
AUC2 (mcg•hr/mL)4.87 ± 1.245.33 ± 1.205.85 ± 1.17**
t½3 (hr)7.24.96.4**
fu (% of dose)-17.1 ± 3.118.4 ± 5.0*NS

1 Comparison was based on t-statistics within repeated measures ANOVA framework. Statistical significance is shown as NS if p > 0.05 and * if p < 0.05

2 AUC0-∞ for single dose and AUC12 for multiple dose data.

3 Harmonic Means.

Pediatric Patients
Children with pharyngitis, otitis media or skin infections

Another study was conducted in pediatric patients and included again both a single dose phase (2 groups, non-fasting and fasting) and multiple dose phase (1 group, fasting) design. It was conducted in 28 infants and children ages 6 months to 10 years with pharyngitis, otitis media or skin infections. The single dose phase involved the administration of a single 7.5 mg/kg dose of clarithromycin granules for suspension (125 mg/5 mL) in either a non-fasting or fasting (2 hours before or 1.5 hours after eating) state.

In the multiple dose phase, patients were given multiple 7.5 mg/kg doses (every 12 hours for 4 or 5 days) of clarithromycin granules for suspension in a fasting state.

A summary of pharmacokinetic parameters is presented in Table 34.

Table 34 Clarithromycin and 14-OH-Clarithromycin Pharmacokinetic Parameters in Pediatric Patients
Parameters Single Dose
Fasting
Mean ± SD
Single Dose
Non-Fasting
Mean ± SD
9th Dose b.i.d.
Fasting
Mean ± SD
(Group I) (Group III) (Group II)
Clarithromycin
Cmax (mcg/mL)3.59 ± 1.474.58 ± 2.764.60 ± 2.08
Tmax (hr)3.1 ± 1.02.8 ± 0.72.8 ± 1.0
Cmin (mcg/mL)--1.67 ± 1.44
Lag (hr)0.60.4-
AUC6 (mcg•hr/mL)10.0 ± 5.4914.2 ± 9.3915.7 ± 6.72
14-OH-Clarithromycin
Cmax (mcg/mL)1.19 ± 0.371.26 ± 0.461.64 ± 0.75
Tmax (hr)3.2 ± 1.04.0 ± 1.02.7 ± 1.7
Cmin (mcg/mL)--1.08 ± 0.84
Lag (hr)0.60.7-
AUC6 (mcg•hr/mL)3.66 ± 1.494.37 ± 1.796.69 ± 2.97

Mean peak plasma clarithromycin and 14-OH metabolite concentrations after single dose administration in a fasting state were 3.59 and 1.19 mg/L, respectively. The differences in Cmax and AUC in the non-fasting and fasting group were not statistically significant. The study shows no deleterious effect of food co-administration on clarithromycin bioavailability in infants and children, similar to results previously noted in adults receiving the tablet formulation.

Mean peak plasma clarithromycin and 14-OH-clarithromycin concentrations after multiple dose (every 12 hours for 4 to 5 days) administration of 7.5 mg/kg of clarithromycin suspension in a fasting state were 4.60 and 1.64 mg/L, respectively. These values compare favourably with those observed in adults after multiple oral dose administration of 250 and 500 mg of clarithromycin. Cmax and AUC increase after multiple dosing as compared with values after single dose administration which is also comparable with data obtained in adults. This indicates that there is no unusual accumulation in infant and children.

Children with secretory otitis media

Multiple oral doses of clarithromycin (7.5 mg/kg every 12 hours for 7 days) were administered to 31 children ages 2 to 12 years with a diagnosis of secretory otitis media. Clarithromycin serum and middle ear effusion (MEE) concentrations were 1.73 ± 1.21 (range 0.16 to 4.96) mg/L and 2.53 ± 2.31 (range 0.39 to 10.62) mg/kg, respectively. In 16 of 24 patients MEE concentrations equalled or exceeded those in serum. The ratio of MEE to serum concentration was 2.48 ± 3.57 (range 0.19 to 15.31).

14-OH-clarithromycin serum and MEE concentrations were 0.82 ± 0.32 (range 0.26 to 1.53) mg/L and 1.27 ± 0.99 (range 0.24 to 4.20) mg/kg, respectively (Table 35). In 14 of 24 patients MEE concentrations equalled or exceeded those in serum. The ratio of MEE to serum concentration was 1.73 ± 1.4 (range 0.25 to 5.87).

Table 35 Clarithromycin Serum and Middle Ear Effusion Concentrationsafter clarithromycin 7.5 mg/kg q12 h for 5 doses
Analyte Serum
(mcg/mL)
Middle Ear Fluid
(mcg/mL)
Clarithromycin 1.7 2.5
14-OH-Clarithromycin 0.8 1.3

When children (n=10) were administered a single oral dose of 7.5 mg/kg suspension, food increased mean plasma clarithromycin concentration from 3.6 (± 1.5) mcg/mL to 4.6 (± 2.8) mcg/mL and the extent of absorption from 10.0 (± 5.5) mcg•hr/mL to 14.2 (± 9.4) mcg•hr/mL.

Although the onset and/or rate of absorption from the suspension formulation is significantly slower than that of the tablet formulation, this is of little clinical relevance.

Microbiology

Clarithromycin exerts its antimicrobial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against various aerobic and anaerobic gram-positive and gram-negative organisms as well as most MAC microorganisms. The in vitro activity of clarithromycin is presented in Table 36.

Additionally, the 14-OH-clarithromycin metabolite also has significant antimicrobial activity which may be additive to the activity of the parent compound. Against Haemophilus influenzae, 14-OH clarithromycin is twice as active as the parent compound in vitro. However, for MAC isolates, the 14-OH metabolite was 4 to 7 times less active than clarithromycin. The clinical significance of this activity against MAC is unknown.

Clarithromycin is bactericidal to H. pylori; this activity is greater at neutral pH than at acid pH.

The ranges of MICs of clarithromycin, 14-OH-clarithromycin metabolite and the MICs required to inhibit 50% (MIC50) and 90% (MIC90) of bacteria are presented in Table 37 and Table 38. Beta-lactamase production should not have any effect on clarithromycin activity.

Cross-resistance to azithromycin has been documented. Attention should be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

The in vitro data indicate enterobacteriaceae, pseudomonas species and other non-lactose fermenting gram negative bacilli are not sensitive to clarithromycin.

Table 36 In Vitro Susceptibility of Strains of Gram-Positive and Gram-Negative Bacteria to Clarithromycin
Microorganisms Number
of
Strains
Cumulative % of Strains Inhibited at MIC (mg/L)
.031 .062 .125 .250 .500 1.00 2.00 4.00 8.00 16.0 32.0 64.0
Gram Positive
Staphylococcus aureus
methicillin resistant
25-4488121212121212100
Staphylococcus aureus
methicillin susceptible
126-20758486878787888888100
All Staphylococcus aureus151-17637273747474757575100
Staphylococcus epidermidis59-18374244454750505454100
Other coagulase negative
staphylococcus
27-14444448484855555959100
Streptococcus pyogenes (GrA)48899193979797100-----
Enterococcus971482559616363646468100
Streptococcus pneumoniae2638848484100-------
Streptococcus agalactiae (GrB)41959595959597100-----
Streptococcus viridans158686869393939393939393100
Other β-hemolytic Streptococcus197878788484848989949494100
Corynebacterium species11274554636363818190100--
Listeria monocytogenes728100----------
Gram Negative
Neisseria gonorrhoeae39233564100--------
Haemophilus influenzae563337163780100----
Neisseria meningitides6-335083100-------
Campylobacter species30-1010438093100-----

* MICs do not take into account the antimicrobial activity of the 14-OH-clarithromycin metabolite.

Table 37 In vitro Susceptibility of Different Bacteria to Clarithromycin
Microorganisms Number
of strains
MIC (mg/L)
Range 50% 90%
Mycoplasma pneumoniae30≤0.004-0.125≤0.004≤0.031
Bordetella pertussis18≤0.008-0.06≤0.0080.03
Legionella pneumophila140.12-0.250.120.25
Haemophilus influenzae222 - 848
Moraxella catarrhalis170.03-0.250.060.25
Chlamydia trachomatis110.002-0.0080.0040.008
Neisseria gonorrhoea260.0625-40.1250.5
Mycobacterium avium304-32816
Mycobacterium avium-
intracellulare
124< 0.25-412
Mycobacterium chelonae137--0.25
Mycobacterium fortuitum86-2.0>8.0
Mycobacterium kansassi24≤0.125-0.25≤0.1250.25
Pasteurella multocida101.0-41.02.0
Bacteriodes melaninogenicus12≤0.125-0.2≤0.125≤0.125
Clostridium perfringens100.25-0.50.50.5
Staphylococcus aureus
(methicillin sensitive)
200.06-0.250.170.24
Streptococcus pyogenes10≤0.06≤0.06≤0.06
Chlamydia pneumoniae490.004-0.0250.0160.031
Helicobacter pylori †130.03-0.060.030.03

† Hardy DJ, Hanson CW, Hensey DM, Beyer JM, Fernandes PB. Susceptibility of Campylobacter pylori to macrolides and fluoroquinolones. J Antimicrob Chemother 1988;22:631-636.

Table 38 In vitro Susceptibility of Different Bacteria to 14-OH-Clarithromycin
Microorganisms Number
of strains
MIC (mg/L)
Range 50% 90%
Streptococcus pyogenes150.015-0.030.0150.03
Streptococcus pneumoniae13≤0.004-0.0150.0080.015
Streptococcus agalactiae150.03-0.060.060.06
Listeria monocytogenes140.25-0.50.50.5
Moraxella catarrhalis170.03-0.120.060.12
Neisseria gonorrhoeae150.06 - 10.250.5
Campylobacter jejuni120.25 - 20.52
Legionella pneumophila140.12 - 0.50.250.5
Haemophilus influenzae221 - 424
Bordetella pertussis18≤0.008-0.060.0150.06
Bacteroides fragilis100.5->12811
Clostridium perfringens100.5 - 0.50.50.5
Propionibacterum acnes120.03->1280.030.06

Clarithromycin Kill Kinetics Against Helicobacter pylori

Figure 7 illustrates the kill kinetics of clarithromycin and 14-OH-clarithromycin against H. pylori at 8 xMIC and at pH 8.0; and Figure 8 illustrates the kill kinetics of clarithromycin and amoxicillin against H. pylori at pH 6.5.



Figure 7: Kill kinetics of clarithromycin and 14-OH-clarithromycin against H. pylori strain 2597 at 8 xMIC and at pH 8.0. A flask was inoculated to produce a starting inoculum of approximately 106 cfu/mL. The flask was then incubated in an anaerobe jar with CampyPak and shaken gently at 37 0C. Counts were done at 0, 2, 4, 8, 24, and 48 h in physiological saline after 72 h incubation. ●, No antimicrobial; ○, clarithromycin (0.12 mg/L); x, 14-OH-clarithromycin (0.24 mg/L).



Figure 8: Kill kinetics of clarithromycin and amoxicillin against H. pylori strain 2597 at pH 6.5. Counts were done at 0, 2, 4, 8, 24, and 48 h in physiological saline after 72 h incubation. ●, No antimicrobial; ○, clarithromycin (3 mg/L); ■, amoxicillin (3 mg/L)

Susceptibility Testing excluding Mycobacteria and Helicobacter

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method43 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder.

The standard single disc susceptibility test (using the 15 mcg clarithromycin disc) and the dilution susceptibility test should be interpreted according to the criteria in Table 39.

Table 39 Criteria for the Interpretation of Standard Single Disc and DilutionSusceptibility Tests except for H. influenzae and H. pylori
Zone Diameter (mm) Appropriate MIC
Correlate (mg/L)
Susceptible ≥ 18 ≤ 2
Intermediate* 14 to 17 4
Resistant ≤ 13 ≥ 8

* Indicates that the test results are equivocal; therefore, dilution tests may be indicated.

N.B. These criteria and the definition are in agreement with NCCLS. Documents M2-A644 and M100-S845.

The standard single disc susceptibility test (using the 15 mcg clarithromycin disc) for H. Influenzae should be interpreted according to the criteria in Table 40.

Table 40 Criteria for the Interpretation of Standard Single Disc and DilutionSusceptibility Tests for H. influenzae
Zone Diameter (mm) Appropriate MIC
Correlate (mg/L)
Susceptible ≥ 13 ≤ 8
Intermediate* 11 to 12 16
Resistant ≤ 10 ≥ 32

* Indicates that the test results are equivocal; therefore, dilution tests may be indicated.

N.B. According to the revised NCCLS 1997 and 1998 Guidelines, the zone diameter and MIC values reflect both the activities of the parent compound and 14-OH metabolite.

A report of "Susceptible" indicates that the pathogen is likely to respond to monotherapy with clarithromycin.

A report of "Intermediate" indicates that the result be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where clarithromycin is physiologically concentrated or in situations where high clarithromycin dosages can be used. This category provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretations.

A report of "Resistant" indicates that achievable drug concentrations are unlikely to be inhibitory, and other therapy should be selected.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure44 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-mcg clarithromycin to test the susceptibility of microorganisms to clarithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-mcg clarithromycin disk should be interpreted according to the criteria in Table 39.

Standardized Dilution Techniques

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values for S. aureus and H. influenzae (Table 41).

Table 41 Standard Clarithromycin Powder MIC Values
Microorganisms MIC (mcg/mL)
S. aureus ATCC 29213 0.12 to 0.5
H. influenzae ATCC 49247 4 to 16

Standardized Diffusion Techniques

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-mcg clarithromycin disk should provide the following zone diameters for S. aureus and H. influenzae (Table 42).

Table 42 Zone Diameter for the 15 mcg Clarithromycin Disc
Microorganisms Zone Diameter (mm)
S. aureus ATCC 25923 26 to 32
H. influenzae ATCC 49247 11 to 17
In vitro Activity of Clarithromycin against Mycobacteria

Clarithromycin has demonstrated in vitro activity against MAC microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on MAC isolates.

Various in vitro methodologies employing broth or solid media at different pH's, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth increases from 5.0 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of OADC in these assays has been shown to further alter MIC values.

Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a microdilution method with Middlebrook 7H9 broth. Results showed MIC values of ≤ 4.0 mcg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value ≤ 0.5 mcg/mL. Clarithromycin activity was evaluated against phagocytized MAC in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In 1 study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Clarithromycin inhibited all isolates at > 10.0 mcg/mL.

Susceptibility Testing for Mycobacterium avium Complex

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values against MAC organisms have not been standardized nor validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to clarithromycin have not been established.

In vitro Activity of Clarithromycin against Helicobacter pylori

Clarithromycin has demonstrated in vitro activity against H. pylori isolated from patients with duodenal ulcers. In vitro susceptibility testing methods (broth microdilution, agar dilution, E-test, and disk diffusion) and diagnostic products currently available for determining MICs and zone sizes have not been standardized, validated, or approved for testing H. pylori. The clarithromycin MIC values and zone sizes will vary depending on the susceptibility testing methodology employed, media, growth additives, pH, inoculum concentration tested, growth phase, incubation atmosphere, and time.

Susceptibility Test for Helicobacter pylori

In vitro susceptibility testing methods and diagnostic products currently available for determining MICs and zone sizes have not been standardized, validated, or approved for testing H. pylori microorganisms. MIC values for H. pylori isolates collected during 2 U.S. clinical trials evaluating clarithromycin plus omeprazole were determined by broth microdilution MIC methodology (Hachem CY et al., 1996). Results obtained during the clarithromycin plus omeprazole clinical trials fell into a distinct bimodal distribution of susceptible and resistant clarithromycin MICs.

If the broth microdilution MIC methodology published in Hachem CY et al., 1996 is used and the following tentative breakpoints are employed, there should be reasonable correlation between MIC results and clinical and microbiological outcomes for patients treated with clarithromycin plus omeprazole (Table 43).

Table 43 Susceptibility Testing for Helicobacter pylori in Patients Treated with Clarithromycin and Omeprazole
MIC (mcg/mL) Interpretation
≤ 0.06 Susceptible (S)
0.12 to 2.0 Intermediate (I)
≥ 4 Resistant (R)

These breakpoints should not be used to interpret results obtained using alternative methods.

Toxicology

Acute Toxicity

Clarithromycin Tablets USP, Film-Coated

The acute toxicity of clarithromycin administered by a variety of routes, was studied in mice and rats. The median lethal dose by the oral route ranged from 2.7 to > 5.0 g/kg. Acute toxicity did not differ markedly between sexes (Table 44).

Table 44 Acute LD50 values of Clarithromycin
Species Sex Route LD50 value (g/kg)
MiceMp.o.2.74
Fp.o.2.7
Ms.c.>5.0
Fs.c.>5.0
Mi.p.1.03
Fi.p.0.85
Mi.v.0.17
Fi.v.0.2
RatsMp.o.3.47
Fp.o.2.7
Ms.c.>5.0
Fs.c.>5.0
Mi.p.6.69
Fi.p.7.58

Legend: i.p. = intraperitoneal; i.v. = intravenous; p.o. = oral; s.c. = subcutaneous.

The primary signs of toxicity included reduction in activities, behaviours, weight gains, respiration rates and sedation. The emetic activity of clarithromycin prevented the determination of the lethal dose in dog.

The acute oral toxicity of clarithromycin in very young mice and rats was determined. The median lethal dose (1.2 g/kg) was about 2-fold that seen in the older rodents.

Clarithromycin for Oral Suspension USP

Clarithromycin was administered orally to rats and mice 3 days after birth. The study design was 10M/10F animals in the dose groups, 20M/20F in the control group. The animals were dosed by gavage with a single dose of a suspension of clarithromycin in 5% gum arabic; control animals received a solution of 5% gum arabic. The recovery period was 14 days.

Mice

The mice were dosed at 714, 857, 1028, 1233, 1480 and 1776 mg/kg; the rats at 769, 1000, 1300, 1690, 2197 and 3713 mg/kg.

LD50 (95% confidence limits) in mice was 1290 mg/kg (1170 to 1420 mg/kg) in males and 1230 mg/kg (1130 to 1340 mg/kg) in females; the sex difference was considered to be negligible. LD50 of clarithromycin orally administered to adult mice is about 2700 mg/kg; acute toxicity was more notable in juvenile animals than in adults. The LD50 of antibiotics of the penicillin group, cephalosporin group and macrolide group is generally lower in juvenile animals than in adults; clarithromycin showed similar results.

Body weight was reduced or its increase was suppressed in both males and females of each dosing group from 1 to 4, 7 or 9 days after the administration, but its changes thereafter were comparable to those in the control group.

Some animals died from 1 to 7 days after the administration. The general condition, suckling behaviour and spontaneous movements were depressed in some of the mice administered 1028 mg/kg or more clarithromycin from 1 day after the administration, but these changes disappeared by 7 days after the administration in those that survived the observation period.

Some animals died from 1 to 7 days after the administration. The general condition, suckling behaviour and spontaneous movements were depressed in some of the mice administered 1028 mg/kg or more clarithromycin from 1 day after the administration, but these changes disappeared by 7 days after the administration in those that survived the observation period.

In the survivors, necropsy showed dilation of renal pelvis in 1 male of the 1028 mg/kg group and hypoplasia of the kidney in 1 female of the 1233 mg/kg group, but these uncommon conditions are considered to be incidental.

Rats

LD50 (95% confidence limits) in rats was 1330 mg/kg (1210 to 1470 mg/kg) in males and 1270 mg/kg (1150 to 1400 mg/kg) in females, the sex difference was considered to be negligible.

LD50 of the agent administered orally to adult rats is about 3000 mg/kg; the acute toxicity was more notable in juvenile animals than in adult animals. LD50 of antibiotics of the penicillin group, cephalosporin group, and macrolide group is generally lower in juvenile animals than in adult animals; clarithromycin showed similar results.

The body weight was reduced or its increase was suppressed in both males and females of each dosing group from 1 to 4 or 7 days after the administration, but body weight changes thereafter were comparable to those of the control group.

Some of the animals of both sexes died from 2 to 5 days after the administration. The general condition, suckling behaviour and spontaneous movements were depressed in some animals from 1 or 2 days after the administration, but in survivors these changes disappeared by 13 days after the administration. In the control group, 1 male and female of the same litter showed depressed suckling behaviour and spontaneous movements from 13 days after the administration, and the female was cannibalised by its mother 14 days after the administration. This is considered to be due to the death of all the other animals of the litter and a resultant reduction in the nursing activity of the mother.

Necropsy of those that died spontaneously showed dark-reddish lungs in about 25%. A reddish-black substance was noted in the intestines of a few males and females of each group administered 2197 mg/kg or more clarithromycin, probably because of bleeding from the intestines. From these findings, the deaths were considered to be due to debilitation resulting from depressed suckling behaviour or bleeding from the intestines.

Necropsy of the survivors revealed nodulated ribs in 1 male of the control group. Since this animal showed a reduction in body weight from 11 days after the administration, these nodules are considered to have been caused by suppressed development of the ribs associated with a delay in the growth. White spots in the liver surface of the 769 mg/kg and 1300 mg/kg groups, and a bulging mass on the surface of the liver and adhesion of the liver to the diaphragm were observed in 1 female of the 769 mg/kg group. Since these changes were infrequent and were not observed in the animals that died during the observation period, they are considered to be incidental.

Three clarithromycin pediatric formulations under consideration for development, a carbopol complex, a hot melt sprayed coating form and a spray-congealed dosage form, were evaluated for acute oral toxicity in rats. Five male and 5 females were administered a single oral dose of 1 of 3 clarithromycin pediatric formulations at a concentration of 250 mg/mL. The dose for all rats was 20 mL/kg (i.e., 5 g/kg). Except for one rat considered to have been misdosed with the spray congealed dosage form, none of the rats died and no signs of toxicity were observed.

No gross morphologic changes were found when the rats were killed and necropsied 2 weeks after treatment.

Doses greater than 5 g/kg were considered to be excessive (5 g/kg is generally employed as the highest test dose for test materials with toxicity too low to determine the minimum lethal dose). Thus, clarithromycin pediatric formulations were found to be non-toxic to rats at the applicable maximum dose of 5 g/kg.

Subchronic Toxicity

Clarithromycin Tablets USP, Film-Coated

Studies were conducted in rats, dogs and monkeys with clarithromycin administered orally. The duration of administration ranged from 14 days to 42 days.

Rats

One study in rats (with oral doses up to 800 mg/kg/day) failed to show adverse effects in rats exposed to 50 mg/kg/day for 4 weeks. The clinical signs observed at toxic doses were reduced motility, piloerection, hypothermia and perineal urine staining. Changes occurred in biochemical parameters at 200 and 800 mg/kg/day indicative of hepatotoxicity which was confirmed by histopathologic findings of hepatocyte necrosis.

Other pathologic findings at the top 2 dose levels included swelling of the renal cortical tubular epithelia and atrophic changes to the lymphatic and genital systems. The same toxicity profile was observed in immature rats following the daily administration of oral doses up to 150 mg/kg/day of clarithromycin for 6 weeks. At 150 mg/kg/day, there was an increase in relative weights of liver and kidneys.

Dogs

Dogs were dosed orally with 0, 6.25, 25, 100 or 400 mg/kg/day of clarithromycin daily for 28 days. Emesis occurred sporadically in the treated dogs. No other adverse effects were seen in dogs exposed to 6.25 mg/kg/day. The clinical signs at higher dosages included loose stools, lacrimation and conjunctivitis.

Slight anorexia was noted in dogs receiving 100 mg/kg/day or more. Dogs at 400 mg/kg/day exhibited reduced red blood cell count, hematocrit, hemoglobin concentration, serum albumin, and mean urine pH and specific gravity. Increases were seen in serum transaminase, alkaline phosphatase, and total bilirubin concentrations.

Bilirubin was detected in the urine. Other pathologic changes at 400 mg/kg/day included biliary hyperplasia, gastric glandular atrophy, renal tubule epithelial atrophy, edema of the iris, ciliary body and choroid, capillary proliferation in the cornea, suppression of spermatogenesis, and adrenal medullary degeneration.

Monkeys

Monkeys were treated daily for 1 month with oral doses of 0, 25, 100 or 400 mg/kg/day. Two animals out of 10 receiving 400 mg/kg/day died. Salivation was recorded at all dosage levels. No other adverse effects were seen in animals treated daily with 25 mg/kg/day.

The clinical signs observed at higher doses and most frequently at 400 mg/kg/day were vomiting, emesis, sunken eyes, dehydration, emaciation, low rectal temperature, body weight loss, reduced food consumption, cloudiness of the cornea and reduction in intra-ocular pressure. Yellow discoloured feces were passed on a few isolated occasions by some animals given a dose of 400 mg/kg/day. As with the other species, the liver was the primary target at toxic doses as shown by early elevation of serum concentration of glucose, BUN, creatinine, ALT, AST, LDH, amylase and/or triglyceride; an electrolyte imbalance and low levels of protein, cholesterol, phospholipid; elevated leucine aminopeptidase (LAP).

Principal histopathologic changes were seen mainly in high dose monkeys, but some mid-dose monkeys exhibited similar alterations. Changes included necrosis and vacuolation of hepatocytes, vacuolation of renal cortical tubules, no spermatogenesis, thymic regression and single cell necrosis of the stomach. In man the recommended dose is 500 to 1000 mg/day or 7.1 to 14.3 mg/kg/day (70 kg person).

Clarithromycin for Oral Suspension USP

Rats

Two-week toxicity study was done with clarithromycin granules administered orally to preweaning rats. Crl:CD*(SD)BR pups, 5 days old at the start of treatment, were dosed by oral gavage with suspension for 17 to 20 days (Table 45).

Table 45 Subchronic Toxicity Study with Clarithromycin Granules Administered Orally to Crl:CD*(SD)BR Preweaning Rats (17 to 20 Treatment Days)
Treatment
Group
Test Material Dosagesa
(mg/kg/day)
Concentrationb
(mg/mL)
No/Group
M F
T0Vehiclec001010
T1Clarithromycin Granule
for Suspension
152.461010
T2Clarithromycin Granule
for Suspension
559.021010
T3Clarithromycin Granule
for Suspension
20032.791010

a Dosages are expressed in terms of the free base.

b In terms of bulk granule (a potency of 610 mcg/mg).

c 0.2% hydroxypropylmethylcellulose (HPMC).

One female pup in the vehicle Control group was found dead on day 18. Sporadic incidence of reddish spots on the skin or skin erythema occurred in some T3 pups. The mean weight gains from days 0 to 17 for T3 males and females were approximately 20 and 10% less than those of T0 males and females, respectively. There were no ophthalmic effects. Statistically significant decreases occurred in the values of mean hemoglobin, mean cell hemoglobin and mean cell volume of T3 male pups (200 mg/kg/day); T3 female pups (200 mg/kg/day) had lower hemoglobin and hematocrit values when compared to controls, but the differences were not significant; similarly the mean hematocrit value of the T3 male pups was also lower than that of the controls. A statistically significant increase was observed in the mean relative kidney weights of T3 pups when compared to controls. Treatment-related minimal to mild multifocal vacuolar degeneration of the intrahepatic bile duct epithelium and an increased incidence of nephritic lesions were observed in the T3 pups (200 mg/kg/day).

A dosage of 200 mg/ kg/day for 2 weeks produced decreased body weight gain, decreased mean hemoglobin and hematocrit values as well as histopathologic changes in the livers and kidneys of preweaning rats. The "no-toxic-effect" dosage in this 2-week preweaning rat study was judged to be 55 mg/kg/day. This finding is similar to that reported following administration to adult rats for 1 month. Preweaning rats did not therefore appear to be more susceptible than mature rats.

Crl:CD*(SD)BR immature rats, aged 15 days at the start of treatment, were dosed daily orally by gavage for 6 weeks. The rats were dosed at 0, 15, 50 and 150 mg/kg clarithromycin, with 10 male and 10 female animals allocated to each treatment group. The control group was treated with 0.2% hydroxypropylmethylcellulose (HPMC) vehicle only.

No deaths occurred during the study. No drug-induced signs were observed. Male T3 pups had a consistently lower mean body weight than male T0 pups on the growth curves. This is considered to be a drug-related effect. Male T3 rats had lower mean food consumption than male T0 rats; male and female T2 rats appear to have consistently higher mean food consumption than male and female T0 rats (not statistically significant). The following increases in relative mean organ weights were observed: liver and kidney of male and female T3 rats, kidney of male T1 rats and spleen of female T3 rats. The increases in liver and kidney relative weights of male and female T3 rats were considered to be drug induced, but no concurrent drug-related micropathology was observed.

Renal hydronephrosis occurred in 1 female T2 rat, which was not considered to be drug-related. A small number of microscopic alterations was distributed randomly through control and treatment groups. None were drug-related.

The "no-toxic effect" level was considered to be 50 mg/kg/day. This finding is similar to administration of clarithromycin to adult rats for 1 month. Immature rats did not, therefore, appear to be more susceptible to clarithromycin than mature rats.

Crl:CD*(SD)BR juvenile rats, 16 days old at the start of treatment, were dosed by oral gavage for 42 to 44 treatment days (Table 46).

Table 46 Subchronic Toxicity Study with Clarithromycin Granules Administered Orally to Crl:CD*(SD)BR Juvenile Rats (42 to 44 treatment days)
Treatment
Group
Test Material Dosagesa
(mg/kg/day)
Concentrationb
(mg/mL)
No/Group
M F
T0Vehiclec001010
T1Clarithromycin Granule
for Suspension
152.441010
T2Clarithromycin Granule
for Suspension
508.131010
T3Clarithromycin Granule
for Suspension
15024.41010

a Dosages are expressed in terms of the free base.

b In terms of bulk granule, Clarithromycin Granule for Suspension with a potency of 615 mcg/mg.

c 0.2% hydroxypropylmethylcellulose (HPMC).

There were no deaths in the study. Excessive salivation occurred in some T3 rats (1 to 2 hours after dosing) during the last 3 weeks of treatment. Male and female pups given 150 mg/kg/day (T3) consistently had lower mean body weights than controls throughout the treatment period. The differences were statistically significant during the first 3 weeks of treatment. The mean weight gains from days 0 to 40 for T3 males and females were 9.4 and 6.9% less than those of T0 males and females, respectively. There were no significant differences between control and drug-treatment groups in food consumption. There were no treatment-related ophthalmic effects.

No meaningful differences were found in urinalyses and hematology parameters for the drug-treated and control rats.

There was a statistically significant decrease in the mean albumin values of T3 male and female rats when compared to controls and a statistically significant increase in the mean relative liver weights for T3 rats when compared to controls. No treatment-related gross or microscopic observations were found. A dosage of 150 mg/kg/day produced slight toxicity in the treated rats. Therefore the no-effect dosage was judged to be 50 mg/kg/day.

Wistar rats, 4 days old at the start of treatment, were dosed by oral gavage for 28 treatment days followed by a 28-day recovery period (Table 47).

Table 47 Subchronic Toxicity Study with Clarithromycin Granules Administered Orally to Wistar Rats (28 treatment days)
Treatment
Group
Test Material Dosagesa
(mg/kg/day)
No/Group
M F
T0Vehicleb02020
T1Clarithromycin12.51212
T2Clarithromycin502020
T3Clarithromycin2002020

a Dosages are expressed in terms of the free base.

b 5% Gum Arabic.

No deaths or abnormalities in the general condition of the animals occurred during the administration or recovery periods in all treated groups.

Body weight gain was suppressed in males and females of the 200 mg/kg group from the 4th day of administration, but normal body weight gain was restored by the discontinuation of the administration. Urinalysis showed slight elevation in pH of the groups administered 50 mg/kg or more clarithromycin, but it was normalized after discontinuation of the administration.

Hematological examinations showed a reduction in haematocrit and a reduction in hemoglobin in both sexes, a reduction in MCHC in males, and a reduction in MCH in females of the 200 mg/kg group. Platelets were reduced in males of the 200 mg/kg group and females of all dosing groups, and white blood cells were reduced in both sexes of the 200 mg/kg group. These changes, however, were reversed or reduced by discontinuation of the administration.

Serum biochemical analyses revealed reduction in AST, ALP, total protein, and albumin in both sexes, a reduction in the calcium level in males, and an elevation in the blood glucose level and reduction in the creatinine level in females of the 200 mg/kg group. These changes, however, could be reversed by discontinuation of the administration.

Necropsy revealed no abnormalities in any of the groups. Concerning organ weights, the absolute and relative weights of the thymus were reduced in males and females of the 200 mg/kg group, but normal weights were restored by discontinuation of the administration.

Changes considered to be related to suppression of body weight gains were observed in the brain, lungs, heart (males only), liver, spleen, kidneys, caecum, and testes (males only) in both sexes of the 200 mg/kg/group. The weight of these organs recovered after discontinuation of the administration. Histopathological studies showed no changes considered to be related to the administration of clarithromycin.

Dogs

Clarithromycin was administered to juvenile beagles by oral catheter daily for 4 weeks at doses of 0 (Control), 30, 100 and 300 mg/kg, followed by a 4-week withdrawal period to evaluate recovery. At the start of the study the beagles were 3 weeks old; each group consisted of 3 males and 3 females; and 1 female and male were added to the control and high-dose groups for the recovery study.

None of the animals died during the administration or recovery period, and no changes in the general condition of the animals were observed.

No changes considered to be due to the administration of clarithromycin were observed in the food consumption, body weight, or the results of ophthalmological, hematological, or serum biochemical examinations. Urinalysis indicated very slight occult blood in 1 female of the high-dose (300 mg/kg) group at the end of the administration period, but it was considered to be unrelated to the administration.

Pathological examinations showed dose-associated reductions in the relative weight of the kidneys in females, but these changes were considered to be unrelated to the administration because individual values were not abnormal. Necropsy revealed no abnormalities. During histological examination, fatty deposition of centrilobular hepatocytes and cell infiltration of portal areas was observed by the light microscopy, and an increase in hepatocellular fat droplets was noted by electron microscopy in the 300 mg/kg group.

In this group, also, increased fat deposition was noted relatively frequently in the kidneys. Other findings, which were considered to be unrelated to the administration, included congestion and megakaryocytic proliferation in the spleen, regional atelectasis and localised lesions of pneumonia in the lungs, leukocytic infiltration around the intrapulmonary bronchi, microfollicular formation of the thyroid glands and reduced stainability (degeneration) of Purkinje cells.

From these findings, the no-effect dose of clarithromycin in a 4-week subacute oral toxicity and a 4-week recovery study in juvenile beagles was considered to be 100 mg/kg for both males and females. The toxic dose was considered to be above 300 mg/kg.

Chronic Toxicity

Clarithromycin Tablets USP, Film-Coated

Rats (20/sex/group) were treated daily with oral doses of 0, 15, 37.5, 75 or 150 mg/kg/day for 3 months. There were 8 incidental deaths, but none of them were considered treatment related. Clinical signs included increased salivation, dehydration, hyperactivity and were observed in a dose-related manner. The only toxic effect noted, was some variation in body weight gain. No toxicologically significant changes occurred in hematology, biochemistry or urinalysis results.

Post mortem, there was an increase in mean relative liver and kidney weights at the top dose level. No microscopic changes were detected in the kidneys, but in the liver, there was a sex/dose-related increase in multinucleated hepatocytes. Effects were only seen in females at 150 mg/kg/day but in males occurred as low as 37.5 mg/kg/day.

A 6-month oral study was performed in rats (20 to 27/sex/group) at dosages of 0, 1 to 6, 8, 40 or 200 mg/kg/ day. Seven male and female rats from the control group and the 40 and 200 mg/kg/day groups were allowed a 63-day non-dosed recovery period. No mortalities occurred. Body weight and food intake were reduced at high doses during the dosing phase but normalized during recovery.

Water intake and urine volume increased in males and females of the 40 and 200 mg/ kg/day groups. Dose-related hematological changes included reduced erythrocytes and HCT with increased MCV, MCH and MCHC and relative eosinophil counts. Biochemical changes were mainly restricted to the high dose group and included increased ALP and decreased phospholipids; decreased total cholesterol and triglycerides, and increased AST and ALT in males only and decreased albumin in females only.

Organ weight increases were found to include cecum, adrenals, liver, and spleen. Histopathological examinations showed drug-related, recovery-reversible increases in multinucleated hepatocytes associated with minimal and focal necrosis in livers of both sexes at the top 2 dose levels. No relevant pathology was found in the cecum, adrenals or spleen to account for the increased weights. After recovery only the 200 mg/kg/day group had increased multinucleated hepatocytes.

Dogs (7/sex/group) were administered daily with oral doses of 0, 10, 30, or 100 mg/kg/day of clarithromycin for 3 months. Emesis occurred at levels of 30 mg/kg and above. One male high-dose dog was killed in extremis on day 69. Drug-related lesions were seen in the liver, gall bladder, thymus and stomach.

Hematological and biochemical changes at the high dose level included, decreased RBC and HCT, increased ALT, ALP, GGT, and decreased total protein and albumin. No significant organ weight changes were recorded, but treatment-related microscopic alterations in the liver and stomach of mild- and high-dose dogs were seen, as well as changes in gall bladder, spleen and thymus of high-dose animals.

A 6-month oral study was also performed in dogs (4 to 5/sex/group) at dosages of 0, 0.8, 4, 20 or 100 mg/kg/day. At the 0 and 100 mg/kg levels, 1 male and 1 female dog were allowed a 1-month, non-dosed, recovery period. One male-high dose dog died on day 174. This death was considered to be as a direct result of clarithromycin administration. Histopathologic examination revealed hepatic parenchymal damage, identifying the cause of clinical jaundice. Clinical signs during the dosing phase of the study were restricted to the top 2 dose levels and included emesis and ocular signs. Food consumption and water intake were reduced at 20 and 100 mg/kg/day.

Hematologic changes at 100 mg/kg were indicative of subclinical anemia. Biochemical alterations at the same level were associated with liver damage. Ocular changes were only apparent at the top dose level.

Increase in the weights of lung, liver, spleen, adrenals and kidneys were found at 100 mg/kg/day. Histopathologic examination of these organs showed degeneration of liver parenchyma, and toxic effects in adrenals. The thymus weight was reduced at 100 mg/kg/day. At the end of the recovery period all findings had regressed or reduced.

Monkeys (5 to 6/sex/group) were similarly administered clarithromycin at levels of 0, 25, 50 or 100 mg/kg/day for 6 months. At the 0 and 100 mg/kg levels, 1 male and 1 female monkey were allowed a one-month recovery period. One high-dose female died in week 25. Inhalation of vomit was considered to be the cause of death. Clinical signs were restricted to a dose-related incidence of emesis and salivation. No treatment-related effects were found in food consumption, ophthalmoscopy or hematology. Weight loss was restricted to 1 high-dose female. Minor serum chemistry changes were seen at the 100 mg/kg level, particularly in plasma proteins. Urinalysis revealed a dose-related lowering of pH and SG at 13 weeks only. Organ weight increases in liver, adrenal and kidneys were seen at high doses, but pathology was restricted to minimal liver changes consisting of cytoplasmic rarefaction of centrilobular hepatocytes. All changes were reversed during the recovery period.

Carcinogenicity

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

Mutagenicity

The following in vitro mutagenicity tests have been conducted with clarithromycin: Salmonella/mammalian microsome test, bacterial induced mutation frequency test, in vitro chromosome aberration test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal study, mouse micronucleus test.

All tests had negative results except the in vitro chromosome aberration test which was weakly positive in one test and negative in another. In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Reproduction and Teratology

Fertility and reproduction studies have shown that daily doses of 150 to160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When given orally after 150 mg/kg/day, clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m2, which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m2.

Special Studies

Acute Renal Toxicity

There was no evidence of nephrotoxicity of clarithromycin in the rat at doses up to 500 mg/kg/day.

Hepatotoxicity

In the in vitro and in vivo hepatotoxicity studies comparing clarithromycin with erythromycin, it was found that clarithromycin caused no greater cytotoxicity than erythromycin stearate and much less toxicity than erythromycin estolate. Hepatic enzyme induction was not found in doses below 500 mg/kg/day. In cynomolgus monkeys, the closest metabolic model for humans, elevations of ALT and LDH were identified at 200 mg/kg/day.

In dogs, a rise of ALT has been seen at 100 mg/kg/day, and in Wistar rats, a similar elevation of enzymes was seen at 200 mg/kg/day. Morphologic lesions related to prolonged exposure to clarithromycin (up to 6 months) have been consistent with reportedly reversible changes in rat, dog and monkey studies. Such doses are many times beyond the therapeutic range in humans, which is within 8 to 10 mg/kg/day.

Ocular Toxicity

Ocular lesions appear confined to dogs and monkeys receiving lethal doses, which were large multiples of the human therapeutic dose. Radiolabelled clarithromycin studies indicate the eye is not selectively burdened by drug deposits and that clearance from this tissue follows that seen in other tissues. Opacities occur in the cornea following widespread extraocular tissue changes which are detectable via numerous diagnostic methods. Reduced intraocular pressure precedes corneal opacity in a relatively predictive manner. Some evidence for transient opacity and at least partial resolution was noted in animal studies, but most animals succumbed to other organ dysfunctions shortly after opacities were observed.

Animals given doses close to the therapeutic dose had no ocular changes. No ophthalmologic effects were noted in rabbits treated at doses of 40 and 160 mg/kg/day for 28 days.

Ototoxicity

No effects on pinna reflex were seen in guinea pigs at a dose of 400 mg/kg/day but inner and outer hair cells disappeared suggesting toxic damage. No evidence of damage was reported at 200 mg/kg/day.