Clarithromycin (Page 4 of 10)

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Acute Hypersensitivity Reactions [see Warnings and Precautions ( 5.1)]
  • QT Prolongation [see Warnings and Precautions ( 5.2)]
  • Hepatotoxicity [see Warnings and Precautions ( 5.3)]
  • Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and Precautions ( 5.4)]
  • Clostridium difficile Associated Diarrhea [see Warnings and Precautions ( 5.6)]
  • Exacerbation of Myasthenia Gravis [see Warnings and Precautions ( 5.8)]

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash.

The subsequent subsections list the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori infection. In general, these profiles are consistent with the pooled data described above.

Prophylaxis of Mycobacterial Infections In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium , it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the clarithromycin group and 8.2 months for the placebo group.

Table 4. Incidence Rates (%) of Selected Adverse Reactions * in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex
*
Includes those events possibly or probably related to study drug and excludes concurrent conditions
2% or greater Adverse Reaction Incidence Rates for either treatment group
Significant higher incidence compared to the placebo-treated group

Body System

Clarithromycin (n=339) %

Placebo (n=339) %

Adverse Reaction

Body as a Whole

Abdominal pain

5%

4%

Headache

3%

1%

Digestive

Diarrhea

8%

4%

Dyspepsia

4%

3%

Flatulence

2%

1%

Nausea

11%

7%

Vomiting

6%

3%

Skin & Appendages

Rash

3%

4%

Special Senses

Taste Perversion

8%

0.3%

Discontinuation due to adverse reactions occurred in 18% of patients receiving clarithromycin compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression, and taste perversion.

Changes in Laboratory Values Selected laboratory adverse experiences that were reported during therapy in greater than 2% of adult patients treated with clarithromycin in a randomized double-blind clinical trial involving 682 patients are presented in Table 5.

In immunocompromised patients receiving prophylaxis against M. avium , evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test.

Table 5. Percentage of Patients * Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex
*
Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables)
ULN= Upper Limit of Normal

Clarithromycin 500 mg twice a day

Placebo

WBC Count

<1 x 10 9 /L

2/103 (4%)

0/95

SGOT

>5 x ULN

7/196 (4%)

5/208 (2%)

SGPT

>5 x ULN

6/217 (3%)

4/232 (2%)

Treatment of Mycobacterial Infections The adverse reaction profiles for both the 500 mg and 1000 mg twice a day dose regimens were similar.

In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.

The following analysis summarizes experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for trial 1 (randomized, double-blind) and trial 2 (open-labeled, compassionate use) and also combined. Adverse reactions were reported less frequently in trial 2, which may be due in part to differences in monitoring between the two studies.

In adult patients receiving clarithromycin 500 mg twice a day, the most frequently reported adverse reactions, considered possibly or possibly related to study drug, with an incidence of 5% or greater, are listed below (Table 6). Approximately 8% of the patients who received 500 mg twice a day and 12% of the patients who received 1000 mg twice a day discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy; adverse reactions leading to discontinuation in at least 2 patients included nausea, vomiting, abdominal pain, diarrhea, rash, and asthenia.

Table 6. Selected Treatment-Related * Adverse Reaction Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg Twice a Day Clarithromycin Dose
*
Includes those events possibly or probably related to study drug and excludes concurrent conditions

Adverse Reaction

Trial 1 (n=53)

Trial 2 (n=255)

Combined (n=308)

Abdominal Pain

8

2

3

Diarrhea

9

2

3

Flatulence

8

0

1

Headache

8

0

2

Nausea

28

9

12

Rash

9

2

3

Taste Perversion

19

0

4

Vomiting

25

4

8

A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse reactions excluding those due to the patient’s concurrent conditions were consistent with those observed in adult patients.

Changes in Laboratory Values
In the first 12 weeks of starting on clarithromycin 500 mg twice a day, 3% of patients has SGOT increases and 2% of patients has SGPT increases > 5 times the upper limit of normal in trial 2 (469 enrolled adult patients) while trial 1 (154 enrolled patients) had no elevation of transaminases. This includes only patients with baseline values within the normal range or borderline low.

Duodenal ulcer associated with H. pylori Infection In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin, no adverse reactions specific to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with clarithromycin, omeprazole or amoxicillin.

The adverse reaction profiles are shown below (Table 7) for four randomized double-blind clinical trials in which patients received the combination of clarithromycin 500 mg three times a day, and omeprazole 40 mg daily for 14 days, followed by omeprazole 20 mg once a day, (three studies) or 40 mg once a day (one study) for an additional 14 days. Of the 346 patients who received the combination, 3.5% of patients discontinued drug due to adverse reactions.

Table 7. Adverse Reactions with an Incidence of 3% or Greater
*
Only two of four studies

Adverse Reaction

Clarithromycin + Omeprazole (n=346) % of Patients

Omeprazole (n=355) % of Patients

Clarithromycin (n=166) % of Patients *

Taste Perversion

15

1

16

Nausea

5

1

3

Headache

5

6

9

Diarrhea

4

3

7

Vomiting

4

<1

1

Abdominal Pain

3

2

1

Infection

3

4

2

Changes in Laboratory Values
Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole in four randomized double-blind trials in 945 patients are as follows:

Hepatic: elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%,
Renal: elevated serum creatinine <1%.

Less Frequent Adverse Reactions Observed During Clinical Trials of Clarithromycin
Based on pooled data across all indications, the following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:

Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocythemia, eosinophilia

Cardiac Disorders: Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations

Ear and Labyrinth Disorders: Vertigo, tinnitus, hearing impaired

Gastrointestinal Disorders: Stomatitis, glossitis, esophagitis, gastroesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence

General Disorders and Administration Site Conditions: Malaise, pyrexia, asthenia, chest pain, chills, fatigue

Hepatobiliary Disorders: Cholestasis, hepatitis

Immune System Disorders: Hypersensitivity

Infections and Infestations: Cellulitis, gastroenteritis, infection, vaginal infection

Investigations: Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal

Metabolism and Nutrition Disorders: Anorexia, decreased appetite

Musculoskeletal and Connective Tissue Disorders: Myalgia, muscle spasms, nuchal rigidity

Nervous System Disorders: Dizziness, tremor, loss of consciousness, dyskinesia, somnolence

Psychiatric Disorders: Anxiety, nervousness

Renal and Urinary Disorders: Blood creatinine increased, blood urea increased

Respiratory, Thoracic and Mediastinal Disorders: Asthma, epistaxis, pulmonary embolism

Skin and Subcutaneous Tissue Disorders: Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular

Gastrointestinal Adverse Reactions
In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse reactions were reported by a similar proportion of patients taking either clarithromycin tablets or clarithromycin extended-release tablets; however, patients taking clarithromycin extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking clarithromycin tablets. In addition, patients taking clarithromycin extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse reactions compared to clarithromycin tablets.

All-Cause Mortality in Patients with Coronary Artery Disease 1 to 10 Years Following Clarithromycin Exposure In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality was observed in patients randomized to clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. Patients were treated with clarithromycin or placebo for 14 days and observed for primary outcome events (e.g., all-cause mortality or non-fatal cardiac events) for several years. 1 A numerically higher number of primary outcome events in patients randomized to receive clarithromycin was observed with a hazard ratio of 1.06 (95% confidence interval 0.98 to 1.14). However, at follow-up 10 years post-treatment, there were 866 (40%) deaths in the clarithromycin group and 815 (37%) deaths in the placebo group that represented a hazard ratio for all-cause mortality of 1.10 (95% confidence interval 1.00 to 1.21). The difference in the number of deaths emerged after one year or more after the end of treatment.

The cause of the difference in all-cause mortality has not been established. Other epidemiologic studies evaluating this risk have shown variable results [see Warnings and Precautions (5.5)].

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