CLARITHROMYCIN tablet, film coated

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
CLARITHROMYCIN (UNII: H1250JIK0A) (CLARITHROMYCIN - UNII:H1250JIK0A)
Available from:
Direct_Rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
1.1 Acute Bacterial Exacerbation of Chronic Bronchitis Clarithromycin tablets, USP are indicated in adults for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae[see Indications and Usage (1.9)] . 1.2 Acute Maxillary Sinusitis Clarithromycin tablets, USP are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae [see Indications and Usage (1.9)] . 1.3 Community-Acquired Pneumonia Clarithromycin tablets, USP are indicated [see Indications and Usage (1.9)] for the treatment of mild to moderate infections caused by susceptible isolates due to: Haemophilus influenzae (in adults) Mycoplasma pneumoniae, Streptococcus pneumoniae, Chlamydophila pneumoniae 1.4 Pharyngitis/Tonsillitis Clarithromycin tablets, USP are indicated for the treatment of mild to moderate
Product summary:
Clarithromycin Tablets, USP are supplied as white to off-white oval film-coated tablets in the following packaging sizes: 250 mg tablets: (imprinted in blue with the “S39” on one side) Bottles of 60 500 mg tablets: (debossed with the “S4” on one side) Bottles of 60 mycin tablets, USP at controlled room temperature 20° to 25°C (68° to 77°F) in a well-closed container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-643-10, 61919-643-20

CLARITHROMYCIN- clarithromycin tablet, film coated

Direct_Rx

----------

CLARITHROMYCIN

1.1 Acute Bacterial Exacerbation of Chronic Bronchitis

Clarithromycin tablets, USP are indicated in adults for the treatment of mild to moderate infections

caused by susceptible isolates due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella

catarrhalis, or Streptococcus pneumoniae[see Indications and Usage (1.9)] .

1.2 Acute Maxillary Sinusitis

Clarithromycin tablets, USP are indicated for the treatment of mild to moderate infections caused by

susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus

pneumoniae [see Indications and Usage (1.9)] .

1.3 Community-Acquired Pneumonia

Clarithromycin tablets, USP are indicated [see Indications and Usage (1.9)] for the treatment of mild to

moderate infections caused by susceptible isolates due to:

Haemophilus influenzae (in adults)

Mycoplasma pneumoniae, Streptococcus pneumoniae, Chlamydophila pneumoniae

1.4 Pharyngitis/Tonsillitis

Clarithromycin tablets, USP are indicated for the treatment of mild to moderate infections caused by

susceptible isolates due to Streptococcus pyogenes as an alternative in individuals who cannot use first

line therapy.

1.5 Uncomplicated Skin and Skin Structure Infections

Clarithromycin tablets, USP are indicated for the treatment of mild to moderate infections caused by

susceptible isolates due to Staphylococcus aureus, or Streptococcus pyogenes.

1.6 Acute Otitis Media

Clarithromycin tablets, USP are indicated in pediatric patients for the treatment of mild to moderate

infections caused by susceptible isolates due to Haemophilus influenzae, Moraxella catarrhalis, or

Streptococcus pneumoniae[see Clinical Studies (14.2)] .

1.7 Treatment and Prophylaxis of Disseminated Mycobacterial Infections

Clarithromycin tablets, USP are indicated for the treatment of mild to moderate infections caused by

susceptible isolates due to Mycobacterium avium or Mycobacterium intracellulare in patients with

advanced HIV infection [see Clinical Studies (14.1)] .

1.8 Helicobacter pylori Infection and Duodenal Ulcer Disease

Clarithromycin tablet, USP is given in combination with other drugs in adults as described below to

eradicate H. pylori. The eradication of H. pylori has been demonstrated to reduce the risk of duodenal

ulcer recurrence [see Clinical Studies (14.3)] .

Clarithromycin tablets, USP in combination with amoxicillin and PREVACID (lansoprazole) or

PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment

of patients with H. pylori infection and duodenal ulcer disease (active or five-year history of duodenal

ulcer) to eradicate H. pylori.

Clarithromycin tablets, USP in combination with PRILOSEC (omeprazole) capsules are indicated for the

treatment of patients with an active duodenal ulcer associated with H. pylori infection. Regimens which

contain clarithromycin tablets, USP as the single antibacterial agent are more likely to be associated

with the development of clarithromycin resistance among patients who fail therapy. Clarithromycin-

containing regimens should not be used in patients with known or suspected clarithromycin resistant

isolates because the efficacy of treatment is reduced in this setting.

1.9 Limitations of Use

There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae

and Staphylococcus aureus. Susceptibility testing should be performed when clinically indicated.

1.10 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin

and other antibacterial drugs, clarithromycin should be used only to treat or prevent infections that are

proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility

information are available, they should be considered in selecting or modifying antibacterial therapy. In

the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric

selection of therapy.

2.1 Important Administration Instructions

Clarithromycin tablets may be given with or without food.

2.2 Adult Dosage

The recommended dosages of clarithromycin for the treatment of mild to moderate infections in adults

are listed in Table 1.

Table 1. Adult Dosage Guidelines

Clarithromycin tablets

Infection Dosage

(every 12 hours) Duration

(days)

Acute bacterial exacerbation of chronic bronchitis 250 to 500 mg a 7 b-14

Acute maxillary sinusitis 500 mg 14

Community-acquired pneumonia 250 mg c 7 d-14

Pharyngitis/Tonsillitis 250 mg 10

Uncomplicated skin and skin structure infections 250 mg 7-14

Treatment and prophylaxis of disseminated Mycobacterium avium disease [see Dosage and

Administration (2.5)] 500 mg e -

H.pylori eradication to reduce the risk of duodenal ulcer recurrence with amoxicillin and omeprazole

or lansoprazole [see Dosage and Administration (2.3)] 500 mg 10-14

H.pylori eradication to reduce the risk of duodenal ulcer recurrence with omeprazole [see Dosage and

Administration (2.3)] 500 mg every 8 hours 14

a For M. catarrhalis and S. pneumoniae use 250 mg. For H. influenzae and H. parainfluenzae, use 500

b For H. parainfluenzae, the duration of therapy is 7 days.

c For H. parainfluenzae and M. catarrhalis use clarithromycin extended-release tablets only.

d For H. influenzae, the duration of therapy is 7 days.

e Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be

discontinued when the patient is considered at low risk of disseminated infection.

2.3 Combination Dosing Regimens for H. pylori Infection

Triple therapy: clarithromycin/lansoprazole/amoxicillin

The recommended adult dosage is 500 mg clarithromycin, 30 mg lansoprazole, and 1 gram amoxicillin,

all given every 12 hours for 10 or 14 days [see Indications and Usage (1.8) and Clinical Studies (14.3)] .

Triple therapy: clarithromycin/omeprazole/amoxicillin

The recommended adult dosage is 500 mg clarithromycin, 20 mg omeprazole, and 1 gram amoxicillin;

all given every 12 hours for 10 days. In patients with an ulcer present at the time of initiation of therapy,

an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom

relief [see Indications and Usage (1.8)and Clinical Studies (14.3)] .

Dual therapy: clarithromycin/omeprazole

The recommended adult dosage is 500 mg clarithromycin given every 8 hours and 40 mg omeprazole

given once every morning for 14 days. An additional 14 days of omeprazole 20 mg once daily is

recommended for ulcer healing and symptom relief [see Indications and Usage (1.8) and Clinical Studies

(14.3)] .

2.4 Pediatric Dosage

The recommended daily dosage is 15 mg/kg/day divided every 12 hours for 10 days (up to the adult

dose). Refer to dosage regimens for mycobacterial infections in pediatric patients for additional dosage

information [see Dosage and Administration (2.5)] .

2.5 Dosage Regimens for Mycobacterial Infections

For the treatment of disseminated infection due to Mycobacterium avium complex (MAC),

clarithromycin is recommended as the primary agents. Clarithromycin should be used in combination

with other antimycobacterial drugs (e.g., ethambutol) that have shown in vitro activity against MAC or

clinical benefit in MAC treatment [see Clinical Studies (14.1)] .

Adult Patients

For treatment and prophylaxis of mycobacterial infections in adults, the recommended dose of

clarithromycin is 500 mg every 12 hours.

Pediatric Patients

For treatment and prophylaxis of mycobacterial infections in pediatric patients, the recommended dose

is 7.5 mg/kg every 12 hours up to 500 mg every 12 hours. [See Use in Specific Populations (8.4) and

Clinical Studies (14.1)] .

Clarithromycin therapy should continue if clinical response is observed. Clarithromycin can be

discontinued when the patient is considered at low risk of disseminated infection.

2.6 Dosage Adjustment in Patients with Renal Impairment

See Table 2 for dosage adjustment in patients with moderate or severe renal impairment with or without

concomitant atazanavir or ritonavir-containing regimens [see Drug Interactions (7)] .

Table 2. Clarithromycin Dosage Adjustments in Patients with Renal Impairment

Recommended Clarithromycin Dosage Reduction

Patients with severe renal impairment (CL cr of <30 mL/min) Reduce the dosage of clarithromycin by

Patients with moderate renal impairment (CL cr of 30 to 60 mL/min) taking concomitant atazanavir or

ritonavir-containing regimens Reduce the dosage of clarithromycin by 50%

Patients with severe renal impairment (CL cr of <30 mL/min) taking concomitant atazanavir or ritonavir-

containing regimens Reduce the dosage of clarithromycin by 75%

2.7 Dosage Adjustment Due to Drug Interactions

Decrease the dose of clarithromycin by 50% when co-administered with atazanavir [see Drug

Interactions (7)] . Dosage adjustments for other drugs when co-administered with clarithromycin may be

recommended due to drug interactions [see Drug Interactions (7)] .

Clarithromycin Tablets USP, 250 mg are white to off-white oval film-coated tablets debossed with

"S39" on one side and blank on the other side.

Clarithromycin Tablets USP, 500 mg are white to off-white oval film-coated tablets debossed with

"S4" on one side and blank on the other side.

4.1 Hypersensitivity

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin,

erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions (5.1)] .

4.2 Cardiac Arrhythmias

Concomitant administration of clarithromycin with cisapride and pimozide is contraindicated [see Drug

Interactions (7)] .

There have been postmarketing reports of drug interactions when clarithromycin is co-administered

with cisapride or pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia,

ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these

drugs by clarithromycin. Fatalities have been reported.

4.3 Cholestatic Jaundice/Hepatic Dysfunction

Clarithromycin is contraindicated in patients with a history of cholestatic jaundice or hepatic

dysfunction associated with prior use of clarithromycin.

4.4 Colchicine

Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or

hepatic impairment.

4.5 HMG-CoA Reductase Inhibitors

Do not use clarithromycin concomitantly with HMG-CoA reductase inhibitors (statins) that are

extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy,

including rhabdomyolysis [see Warnings and Precautions (5.4) and Drug Interactions (7)] .

4.6 Ergot Alkaloids

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated

[see Drug Interactions (7)] .

4.7 Contraindications for Co-administered Drugs

For information about contraindications of other drugs indicated in combination with clarithromycin,

refer to their full prescribing information (contraindications section).

5.1 Acute Hypersensitivity Reactions

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome,

toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-

Schonlein purpura, and acute generalized exanthematous pustulosis, discontinue clarithromycin therapy

immediately and institute appropriate treatment.

5.2 QT Prolongation

Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of

arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing

surveillance in patients receiving clarithromycin. Fatalities have been reported.

Avoid clarithromycin in the following patients:

patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades

de pointes

patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2)]

patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia,

clinically significant bradycardia and in patients receiving Class IA (quinidine, procainamide) or Class

III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Use in

Specific Populations (8.5)] .

5.3 Hepatotoxicity

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis,

with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be

severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported

and generally has been associated with serious underlying diseases and/or concomitant medications.

Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur.

5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs

Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking

clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with

colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with

disopyramide; hypotension and acute kidney injury with calcium channel blockers metabolized by

CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with

calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older.

Use clarithromycin with caution when administered concurrently with medications that induce the

cytochrome CYP3A4 enzyme. The use of clarithromycin with simvastatin, lovastatin, ergotamine, or

dihydroergotamine is contraindicated [see Contraindications (4.5,4.6) and Drug Interactions (7)] .

Colchicine: Life-threatening and fatal drug interactions have been reported in patients treated with

clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may

occur while using both drugs at their recommended doses. If co-administration of clarithromycin and

colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of

colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of

clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment [see

Contraindications (4.4) and Drug Interactions (7)] .

HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or

simvastatin is contraindicated [see Contraindications (4.5)] as these statins are extensively metabolized

by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which

increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported

in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot

be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.

Exercise caution when prescribing clarithromycin with atorvastatin or pravastatin. In situations where

the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin

dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin

that is not dependent on CYP3A metabolism (e.g., fluvastatin) can be considered. It is recommended to

prescribe the lowest registered dose if concomitant use cannot be avoided.

Oral Hypoglycemic Agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic

agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as

nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin

may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of

glucose is recommended [see Drug Interactions (7)] .

Quetiapine: Use quetiapine and clarithromycin concomitantly with caution. Co-administration could

result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic

hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation.

Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered

with CYP3A4 inhibitors such as clarithromycin [see Drug Interactions (7)] .

Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and

prothrombin time when clarithromycin is co-administered with warfarin. Monitor INR and prothrombin

times frequently while patients are receiving clarithromycin and oral anticoagulants concurrently [see

Drug Interactions (7)] .

Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant

administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam [see

Drug Interactions (7)] .

5.5 All-Cause Mortality in Patients With Coronary Artery Disease 1 to 10 Years After 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 one year or more after the end of treatment was

observed in patients randomized to receive clarithromycin. 1 Clarithromycin for treatment of coronary

artery disease is not an approved indication. The cause of the increased risk has not been established.

Other epidemiologic studies evaluating this risk have shown variable results [see Adverse Reactions

(6.1)] . Consider balancing this potential risk with the treatment benefits when prescribing

clarithromycin in patients who have suspected or confirmed coronary artery disease.

5.6 Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial

agents, including clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment

with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin

producing strains of C. difficile cause increased morbidity and mortality, as these infections can be

refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients

who present with diarrhea following antibacterial use. Careful medical history is necessary since

CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need

to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial

treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.7 Embryofetal Toxicity

Clarithromycin should not be used in pregnant women except in clinical circumstances where no

alternative therapy is appropriate. If clarithromycin is used during pregnancy, or if pregnancy occurs

while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus.

Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal

development in monkeys, rats, mice, and rabbits at doses that produced plasma levels 2 times to 17 times

the serum levels achieved in humans treated at the maximum recommended human doses [see Use in

Specific Populations (8.1)] .

5.8 Exacerbation of Myasthenia Gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has

been reported in patients receiving clarithromycin therapy.

5.9 Development of Drug Resistant Bacteria

Prescribing clarithromycin in the absence of a proven or strongly suspected bacterial infection or a

prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the

development of drug-resistant bacteria.

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 a in Immunocompromised Adult Patients

Receiving Prophylaxis Against M. avium Complex

Body System b

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% c 0.3%

a Includes those events possibly or probably related to study drug and excludes concurrent conditions

b 2% or greater Adverse Reaction Incidence Rates for either treatment group

c Significant higher incidence compared to the placebo-treated group

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 a Exceeding Extreme Laboratory Values in Patients Receiving

Prophylaxis Against M. avium Complex

Clarithromycin 500 mg

twice a day Placebo

WBC Count <1 x 10 9/L 2/103 (4%) 0/95

SGOT >5 x ULN b 7/196 (4%) 5/208 (2%)

SGPT >5 x ULN b 6/217 (3%) 4/232 (2%)

a Includes only patients with baseline values within the normal range or borderline high (hematology

variables) and within normal range or borderline low (chemistry variables)

b ULN= Upper Limit of Normal

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 a Adverse Reaction Incidence Rates (%) in Immunocompromised

Adult Patients During the First 12 Weeks of Therapy with 500 mg Twice a Day Clarithromycin Dose

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 Includes those events possibly or probably related to study drug and excludes concurrent conditions

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

Adverse Reaction Clarithromycin + Omeprazole

(n=346)

% of Patients Omeprazole

(n=355)

% of Patients Clarithromycin

(n=166)

% of Patients a

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

a Only two of four studies

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, gastrooesophageal 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)] .

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-appr use of clarithromycin. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: Thrombocytopenia, agranulocytosis

Cardiac: Ventricular arrhythmia, ventricular tachycardia, torsades de pointes

Ear and Labyrinth: Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal: Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was

usually reversible with professional cleaning upon discontinuation of the drug.

There have been reports of clarithromycin extended-release tablets in the stool, many of which have

occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal

disorders with shortened GI transit times. In several reports, tablet residues have occurred in the

context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no

improvement in their condition should be switched to a different clarithromycin formulation (e.g.

suspension) or another antibacterial drug.

Hepatobiliary: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic

dysfunction have been reported with clarithromycin [see Warnings and Precautions (5.2)] .

Infections and Infestations: Pseudomembranous colitis [see Warnings and Precautions (5.6)]

Immune System: Anaphylactic reactions, angioedema

Investigations: Prothrombin time prolonged, white blood cell count decreased, international normalized

ratio increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and Nutrition: Hypoglycemia has been reported in patients taking oral hypoglycemic agents

or insulin.

Musculoskeletal and Connective Tissue: Myopathy rhabdomyolysis was reported and in some of the

reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol

[see Contraindications (4.5) and Warnings and Precautions (5.4)] .

Nervous System: Parosmia, anosmia, ageusia, paresthesia and convulsions

Psychiatric: Abnormal behavior, confusional state, depersonalization, disorientation, hallucination,

depression, manic behavior, abnormal dream, psychotic disorder. These disorders usually resolve upon

discontinuation of the drug.

Renal and Urinary: Nephritis interstitial, renal failure

Skin and Subcutaneous Tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with

eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne, acute generalized

exanthematous pustulosis

Vascular: Hemorrhage

Co-administration of clarithromycin is known to inhibit CYP3A, and a drug primarily metabolized by

CYP3A may be associated with elevations in drug concentrations that could increase or prolong both

therapeutic and adverse effects of the concomitant drug.

Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be

CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g.,

carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Adjust dosage when

appropriate and monitor serum concentrations of drugs primarily metabolized by CYP3A closely in

patients concurrently receiving clarithromycin.

Table 8: Clinically Significant Drug Interactions with Clarithromycin

Drugs That Are Affected By Clarithromycin

Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments

Antiarrhythmics:

Disopyramide

Quinidine

Dofetilide

Amiodarone

Sotalol

Procainamide Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of

torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide.

Electrocardiograms should be monitored for QTc prolongation during coadministration of

clarithromycin with these drugs [see Warnings and Precautions (5.3)] .

Serum concentrations of these medications should also be monitored. There have been spontaneous or

published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.

There have been postmarketing reports of hypoglycemia with the concomitant administration of

clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during

concomitant administration of clarithromycin and disopyramide.

Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin

is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by

clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in

patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing

surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including

potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered,

especially for patients with digoxin concentrations in the upper therapeutic range.

Oral Anticoagulants:

Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period

suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the

effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are

receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .

Antiepileptics:

Carbamazepine Use With Caution Carbamazepine: Concomitant administration of single doses of

clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of

carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum

concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been

spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.

Antifungals:

Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and

inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered

concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below).

Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and

clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or

prolonged adverse reactions.

Fluconazole No Dose Adjustment

Fluconazole: [see Pharmacokinetics (12.3)]

Anti-Gout Agents:

Colchicine (in patients with renal or hepatic impairment)

Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-

glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The

dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal

renal and hepatic function [see Contraindications (4.4)and Warnings and Precautions (5.4)] .

Colchicine (in patients with normal renal and hepatic function) Use With Caution

Antipsychotics:

Pimozide Contraindicated Pimozide:[See Contraindications (4.2)]

Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-

administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine

related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension,

altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during

concomitant administration. Refer to quetiapine prescribing information for recommendations on dose

reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.

Antispasmodics:

Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route

of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of

CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of

CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice

daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-

administered with clarithromycin.

Antivirals:

Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors

of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That

Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .

Saquinavir (in patients with decreased renal function) Saquinavir: Both clarithromycin and saquinavir are

substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see

Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .

Ritonavir

Etravirine Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin”

in the table below) [see Pharmacokinetics (12.3)] .

Maraviroc Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of

CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given

with strong CYP3A inhibitors such as clarithromycin.

Boceprevir (in patients with normal renal function)

Didanosine No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and

inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No

dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing

information).

Zidovudine Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets

and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine

concentrations. Administration of clarithromycin and zidovudine should be separated by at least two

hours [see Pharmacokinetics (12.3)] .

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine

has not been evaluated.

Calcium Channel Blockers:

Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been

observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .

Amlodipine

Diltiazem

Amlodipine, Diltiazem:[See Warnings and Precautions (5.4)]

Nifedipine Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are

known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and

clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken

concomitantly with nifedipine [see Warnings and Precautions (5.4)] .

Ergot Alkaloids:

Ergotamine

Dihydroergotamine Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate

that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with

acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues

including the central nervous system [see Contraindications (4.6)] .

Gastroprokinetic Agents:

Cisapride Contraindicated Cisapride:[See Contraindications (4.2)]

HMG-CoA Reductase Inhibitors:

Lovastatin

Simvastatin Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin:[See

Contraindications (4.5)and Warnings and Precautions (5.4)]

Atorvastatin

Pravastatin

Use With Caution

Fluvastatin

No Dose Adjustment

Hypoglycemic Agents:

Nateglinide

Pioglitazone

Repaglinide

Rosiglitazone

Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone:[See Warnings and Precautions

(5.4)and Adverse Reactions (6.2)]

Insulin Insulin:[See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]

Immunosuppressants:

Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of

CYP3A based interactions of clarithromycin with cyclosporine.

Tacrolimus Tacrolimus: There have been spontaneous or published reports of CYP3A based

interactions of clarithromycin with tacrolimus.

Phosphodiesterase inhibitors:

Sildenafil

Tadalafil

Vardenafil Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase

inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant

administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or

vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of

these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic

exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase

inhibitors should be considered (see their respective prescribing information).

Proton Pump Inhibitors:

Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when

omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of

increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs

That Affect Clarithromycin” in the table below).

Xanthine Derivatives:

Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving

theophylline may be associated with an increase of serum theophylline concentrations [see

Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for

patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic

range.

Triazolobenzodiazepines and Other Related Benzodiazepines:

Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin,

dose adjustments may be necessary and possible prolongation and intensity of effect should be

anticipated [see Warnings and Precautions (5.4)and Pharmacokinetics (12.3)] .

Alprazolam

Triazolam Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when

triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports

of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the

concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS

pharmacological effects is suggested.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and

midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

Temazepam

Nitrazepam

Lorazepam No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are

not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction

with clarithromycin is unlikely.

Cytochrome P450 Inducers:

Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin

resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an

increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).

Other Drugs Metabolized by CYP3A:

Alfentanil

Bromocriptine

Cilostazol

Methylprednisole

Vinblastine

Phenobarbital

St. John’s Wort

Use With Caution There have been spontaneous or published reports of CYP3A based interactions of

clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital,

and St. John’s Wort.

Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:

Hexobarbital

Phenytoin

Valproate Use With Caution There have been postmarketing reports of interactions of clarithromycin

with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.

Drugs that Affect Clarithromycin

Drug(s) that Affect the Pharmacokinetics of Clarithromycin Recommendation Comments

Antifungals:

Itraconazole

Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin.

Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or

symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are

Affected By Clarithromycin” in the table above).

Antivirals:

Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the

dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] .

Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-

administered with atazanavir, alternative antibacterial therapy should be considered for indications other

than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg

per day should not be co-administered with protease inhibitors.

Ritonavir (in patients with decreased renal function) Ritonavir: Since concentrations of 14-OH

clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir,

alternative antibacterial therapy should be considered for indications other than infections due to

Mycobacterium avium[see Pharmacokinetics (12.3)] .

Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease

inhibitors.

Saquinavir (in patients with decreased renal function) Saquinavir: When saquinavir is co-administered

with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin

(refer to ritonavir above) [see Pharmacokinetics (12.3)] .

Etravirine Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of

the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has

reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen

may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

Saquinavir (in patients with normal renal function) No Dose Adjustment

Ritonavir (in patients with normal renal function)

Proton Pump Inhibitors:

Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and

mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .

Miscellaneous Cytochrome P450 Inducers:

Efavirenz

Nevirapine

Rifampicin

Rifabutin

Rifapentine Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin,

rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma

concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the

microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different

bacteria, the intended therapeutic effect could be impaired during concomitant administration of

clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when

treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of

CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are

Affected By Clarithromycin” in the table above).

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

Clarithromycin should not be used in pregnant women except in clinical circumstances where no

alternative therapy is appropriate. If pregnancy occurs while taking this drug, the patient should be

apprised of the potential hazard to the fetus [see Warnings and Precautions (5.7)] .

Four teratogenicity studies in rats (three with oral doses and one with intravenous doses up to 160

mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to

125 mg/kg/day (approximately twice the recommended maximum human dose based on mg/m 2) or

intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18 failed to demonstrate any

teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at similar doses

and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150

mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day were twice the

human serum levels. Four studies in mice revealed a variable incidence of cleft palate following oral

doses of 1000 mg/kg/day (2 and 4 times the recommended maximum human dose based on mg/m 2,

respectively) during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000

mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose

of 70 mg/kg/day produced fetal growth retardation at plasma levels that were twice the human serum

levels.

8.3 Nursing Mothers

Caution should be exercised when clarithromycin is administered to nursing women. The development

and health benefits of human milk feeding should be considered along with the mother’s clinical need

for clarithromycin and any potential adverse effects on the human milk fed child from the drug or from

the underlying maternal condition.

Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk. Serum

and milk samples were obtained after 3 days of treatment, at steady state, from one published study of 12

lactating women who were taking clarithromycin 250 mg orally twice daily. Based on the limited data

from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk fed infant

would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with

this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day,

based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day)

for children greater than 6 months of age.

A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibacterial (6

were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin.

Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants

exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.

8.4 Pediatric Use

The safety and effectiveness of clarithromycin tablets have been established for the treatment of the

following conditions or diseases in pediatric patients 6 months and older. Use in these indications is

based on clinical trials in pediatric patients or adequate and well-controlled studies in adults with

additional pharmacokinetic and safety data in pediatric patients:

Pharyngitis/Tonsillitis

Community-Acquired Pneumonia

Acute maxillary sinusitis

Acute otitis media [see Clinical Studies (14.2)]

Uncomplicated skin and skin structure infections

The safety and effectiveness of clarithromycin tablets have been established for the prevention of

disseminated Mycobacterium avium complex (MAC) disease in pediatric patients 20 months and older

with advanced HIV infection. No studies of clarithromycin for MAC prophylaxis have been performed

in pediatric populations and the doses recommended for prophylaxis are derived from MAC pediatric

treatment studies.

Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been

established. The safety of clarithromycin has not been studied in MAC patients under the age of 20

months.

8.5 Geriatric Use

In a steady-state study in which healthy elderly subjects (65 years to 81 years of age) were given 500

mg of clarithromycin every 12 hours, the maximum serum concentrations and area under the curves of

clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young

adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In

clinical trials, elderly patients did not have an increased incidence of adverse reactions when compared

to younger patients. Consider dosage adjustment in elderly patients with severe renal impairment.

Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than

younger patients [see Warnings and Precautions (5.3)] .

Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g.,

verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older [see

Warnings and Precautions (5.4)] .

Especially in elderly patients, there have been reports of colchicine toxicity with concomitant use of

clarithromycin and colchicine, some of which occurred in patients with renal insufficiency. Deaths have

been reported in some patients [see Contraindications (4.4)and Warnings and Precautions (5.4)] .

8.6 Renal and Hepatic Impairment

Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered

without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the

presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage

or prolonged dosing intervals may be appropriate [see Dosage and Administration (2.5)] .

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting,

nausea, and diarrhea.

Treat adverse reactions accompanying overdosage by the prompt elimination of unabsorbed drug and

supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected

to be appreciably affected by hemodialysis or peritoneal dialysis.

Clarithromycin is a semi-synthetic macrolide antimicrobial for oral use. Chemically, it is 6- 0-

methylerythromycin. The molecular formula is C 38H 69NO 13, and the molecular weight is 747.96.

The structural formula is:

[chemical structure]

Figure 1: Structure of Clarithromycin

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in

methanol, ethanol, and acetonitrile, and practically insoluble in water.

Each white to off-white oval film-coated immediate-release clarithromycin tablet, USP contains 250 mg

or 500 mg of clarithromycin and the following inactive ingredients: croscarmellose sodium, magnesium

stearate, microcrystalline cellulose, povidone, silicon dioxide, hypromellose, titanium dioxide and

polyethylene glycol.

12.1 Mechanism of Action

Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12.4)] .

12.3 Pharmacokinetics

Absorption

The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500

mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the

peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma

concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does

not affect the onset of formation of the active metabolite, 14-OH clarithromycin or its peak plasma

concentration but does slightly decrease the extent of metabolite formation, indicated by an 11%

decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets

may be given without regard to food. In non-fasting healthy human subjects (males and females), peak

plasma concentrations were attained within 2 to 3 hours after oral dosing.

Distribution

Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids.

There are no data available on cerebrospinal fluid penetration. Because of high intracellular

concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue and

serum concentrations are presented below.

Table 9. Tissue and Serum Concentrations of Clarithromycin

CONCENTRATION (after 250 mg every 12 hours)

Tissue Type Tissue

(mcg/g) Serum

(mcg/mL)

Tonsil 1.6 0.8

Lung 8.8 1.7

Metabolism and Elimination

Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were

approximately 1 mcg/mL to 2 mcg/mL with a 250 mg dose administered every 12 hours and 3 mcg/mL to

4 mcg/mL with a 500 mg dose administered every 8 hours to 12 hours. The elimination half-life of

clarithromycin was about 3 hours to 4 hours with 250 mg administered every 12 hours but increased to

5 hours to 7 hours with 500 mg administered every 8 hours to 12 hours. The nonlinearity of

clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg

administered every 8 hours to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite,

14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 mcg/mL and has an

elimination half-life of 5 hours to 6 hours. With a 500 mg every 8 hours to 12 hours dosing, the peak

steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 mcg/mL), and its

elimination half-life is about 7 hours to 9 hours. With any of these dosing regimens, the steady-state

concentration of this metabolite is generally attained within 3 days to 4 days.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as

clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is

somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL)

suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. 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 either a 250 mg or a 500 mg tablet administered

every 12 hours.

Specific Populations

Pediatric Patients

Clarithromycin penetrates into the middle ear fluid of pediatric patients with secretory otitis media.

Table 10. Middle Ear Fluid and Serum Concentrations of Clarithromycin and 14-OH-Clarithromycin in

Pediatric Patients

CONCENTRATION (after 7.5 mg/kg every 12 hours for 5 doses)

Analyte Middle Ear Fluid

(mcg/mL) Serum

(mcg/mL)

Clarithromycin 2.5 1.7

14-OH Clarithromycin 1.3 0.8

When pediatric patients (n = 10) were administered a single oral dose of 7.5 mg/kg clarithromycin as an

oral suspension, food increased mean peak plasma clarithromycin concentrations from 3.6 (± 1.5)

mcg/mL to 4.6 (± 2.8) mcg/mL and the extent of absorption from 10.0 (± 5.5) hrmcg/mL to 14.2 (± 9.4)

hrmcg/mL.

In pediatric patients requiring antibacterial therapy, administration of 7.5 mg/kg every 12 hours of

clarithromycin as an oral suspension generally resulted in steady-state peak plasma concentrations of 3

mcg/mL to 7 mcg/mL for clarithromycin and 1 mcg/mL to 2 mcg/mL for 14-OH clarithromycin.

In HIV-infected pediatric patients taking 15 mg/kg of clarithromycin as an oral suspension every 12

hours, steady-state clarithromycin peak concentrations generally ranged from 6 mcg/mL to 15 mcg/mL.

HIV Infection

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following

administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection

were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500-mg or

1000-mg doses of clarithromycin every 12 hours, steady-state clarithromycin C max values ranged

from 2 mcg/mL to 4 mcg/mL and 5 mcg/mL to 10 mcg/mL, respectively.

Hepatic Impairment

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.

Renal Impairment

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function [see

Use in Specific Populations (8.6)and Dosage and Administration (2.5)] .

Drug Interactions

Fluconazole

Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21

healthy volunteers, the steady-state clarithromycin C min and AUC increased 33% and 18%,

respectively. Clarithromycin exposures were increased and steady-state concentrations of 14-OH

clarithromycin were not significantly affected by concomitant administration of fluconazole.

Colchicine

When a single dose of colchicine 0.6 mg was administered with clarithromycin 250 mg BID for 7 days,

the colchicine C max increased 197% and the AUC 0-∞ increased 239% compared to administration of

colchicine alone.

Atazanavir

Following administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily),

the clarithromycin AUC increased 94%, the 14-OH clarithromycin AUC decreased 70% and the

atazanavir AUC increased 28%.

Ritonavir

Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in

clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin.

Saquinavir

Following administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg

tid) to 12 healthy volunteers, the steady-state saquinavir AUC and C max increased 177% and 187%

respectively compared to administration of saquinavir alone. Clarithromycin AUC and C max increased

45% and 39% respectively, whereas the 14–OH clarithromycin AUC and C max decreased 24% and

34% respectively, compared to administration with clarithromycin alone.

Didanosine

Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients

resulted in no statistically significant change in didanosine pharmacokinetics.

Zidovudine

Following administration of clarithromycin 500 mg tablets twice daily with zidovudine 100 mg every 4

hours, the steady-state zidovudine AUC decreased 12% compared to administration of zidovudine alone

(n=4). Individual values ranged from a decrease of 34% to an increase of 14%. When clarithromycin

tablets were administered two to four hours prior to zidovudine, the steady-state zidovudine C max

increased 100% whereas the AUC was unaffected (n=24).

Omeprazole

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy

adult subjects. The steady-state plasma concentrations of omeprazole were increased (C max, AUC 0-

24, and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of

clarithromycin.

The plasma levels of clarithromycin and 14–OH clarithromycin were increased by the concomitant

administration of omeprazole. For clarithromycin, the mean C max was 10% greater, the mean C min was

27% greater, and the mean AUC 0-8 was 15% greater when clarithromycin was administered with

omeprazole than when clarithromycin was administered alone. Similar results were seen for 14–OH

clarithromycin, the mean C max was 45% greater, the mean C min was 57% greater, and the mean AUC

0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also

increased by concomitant administration of omeprazole.

Clarithromycin Tissue Concentrations 2 hours after Dose (mcg/mL)/(mcg/g)

Treatment N antrum fundus N Mucus

Clarithromycin 5 10.48 ± 2.01 20.81 ± 7.64 4 4.15 ± 7.74

Clarithromycin + Omeprazole 5 19.96 ± 4.71 24.25 ± 6.37 4 39.29 ± 32.79

Theophylline

In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-

release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h

clarithromycin), the steady-state levels of C max, C min, and the area under the serum concentration time

curve (AUC) of theophylline increased about 20%.

Midazolam

When a single dose of midazolam was co-administered with clarithromycin tablets (500 mg twice daily

for 7 days), midazolam AUC increased 174% after intravenous administration of midazolam and 600%

after oral administration.

For information about other drugs indicated in combination with clarithromycin, refer to their full

prescribing information, CLINICAL PHARMACOLOGY section.

12.4 Microbiology

Mechanism of Action

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible

bacteria resulting in inhibition of protein synthesis.

Resistance

The major routes of resistance are modification of the 23S rRNA in the 50S ribosomal subunit to

insensitivity or drug efflux pumps. Beta-lactamase production should have no effect on clarithromycin

activity.

Most isolates of methicillin-resistant and oxacillin-resistant staphylococci are resistant to

clarithromycin.

If H. pylori is not eradicated after treatment with clarithromycin-containing combination regimens,

patients may develop clarithromycin resistance in H. pylori isolates. Therefore, for patients who fail

therapy, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin-

resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual

therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin

triple therapy; or other regimens which include clarithromycin as the sole antibacterial agent.

Antimicrobial Activity

Clarithromycin has been shown to be active against most of the isolates of the following

microorganisms both in vitro and in clinical infections [see Indications and Usage (1)] .

Gram-Positive Bacteria

Staphylococcus aureus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-Negative Bacteria

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Other Microorganisms

Chlamydophila pneumoniae

Helicobacter pylori

Mycobacterium avium complex (MAC) consisting of M. avium and M. intracellulare

Mycoplasma pneumoniae

At least 90 percent of the microorganisms listed below exhibit in vitro minimum inhibitory

concentrations (MICs) less than or equal to the clarithromycin susceptible MIC breakpoint for

organisms of similar type to those shown in Table 11. However, the efficacy of clarithromycin in

treating clinical infections due to these microorganisms has not been established in adequate and well-

controlled clinical trials.

Gram-Positive Bacteria

Streptococcus agalactiae

Streptococci (Groups C, F, G)

Viridans group streptococci

Gram-Negative Bacteria

Legionella pneumophila

Pasteurella multocida

Anaerobic Bacteria

Clostridium perfringens

Peptococcus niger

Prevotella melaninogenica

Propionibacterium acnes

Susceptibility Testing Methods (Excluding Mycobacteria and Helicobacter)

When available, the clinical microbiology laboratory should provide the results of in vitro

susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the

physician as periodic reports that describe the susceptibility profile of nosocomial and community-

acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug for

treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs).

These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs

should be determined using a standardized test method 2,3 (broth and/or agar). The MIC values should

be interpreted according to the criteria provided in Table 11.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible

estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be

determined using a standardized test method. 3,4 This procedure uses paper disks impregnated with 15

mcg of clarithromycin to test the susceptibility of bacteria to clarithromycin. The disk diffusion

interpretive criteria are provided in Table 11.

Susceptibility Testing for Mycobacterium avium Complex (MAC)

The reference methodology for susceptibility testing of Mycobacterium avium complex (MAC) is

broth dilution (either microdilution or macrodilution method). 5 For broth microdilution testing, cation-

adjusted Mueller-Hinton broth (CAMHB) supplemented with 5% OADC is recommended. Transparent

colonies should be used for the inoculum, if present. Susceptibility testing at either pH 6.8 or pH 7.4 is

acceptable, provided that interpretation is done based on the culture conditions employed. Microdilution

trays are incubated at 35 ºC to 37 ºC in ambient air and examined after seven days. Trays should be

incubated and read again at 10 to 14 days, if growth is poor on initial inspection.

Susceptibility Testing for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. 6 One to three

microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10 7-1 x 10 8 CFU/mL for H.

pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar

plates with 5% aged defibrinated sheep blood (> 2-weeks old). The agar dilution plates are incubated at

35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter

species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial

agent required to inhibit growth of the organism. The clarithromycin MIC values should be interpreted

according to the criteria in Table 11.

Table 11. Susceptibility Test Interpretive Criteria for Clarithromycin

Minimum Inhibitory

Concentrations (mcg/mL) Disk Diffusion

(zone diameters in mm)

Pathogen S I R S I R

Staphylococcus aureus ≤ 2 4 ≥ 8 ≥ 18 14--17 ≤ 13

Streptococcus pyogenes and Streptococcus pneumoniae ≤ 0.25 a 0.5 a ≥ 1 a ≥ 21 b 17--20 b ≤ 16 b

Haemophilus influenzae ≤ 8 c 16 c ≥ 32 c ≥ 13 d 11--12 d ≤ 10 d

Helicobacter pylorie ≤ 0.25 0.5 ≥ 1 -- -- --

a These interpretive standards are applicable only to broth microdilution susceptibility tests using

cation adjusted Mueller Hinton broth with 2-5% lysed horse blood 3.

b These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented

with 5% sheep blood incubated in 5% CO 23.

c These interpretive standards are applicable only to broth microdilution susceptibility tests with

Haemophilus spp. using Haemophilus Testing Medium (HTM) 3.

d These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM 3.

e These are tentative breakpoints for clarithromycin for the agar dilution methodology and should not

be used to interpret results obtained using alternative methods 6.

Note: When testing Streptococcus pyogenes and Streptococcus pneumoniae, susceptibility and

resistance to clarithromycin can be predicted using erythromycin.

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the

pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection.

A report of Intermediate (I) indicates that the result should 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 the drug is

physiologically concentrated or in situations where high dosage of drug can be used. This category

also provides a buffer zone which prevents small uncontrolled technical factors from causing major

discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not

likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually

achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory control bacteria to monitor and

ensure the accuracy and precision of supplies and reagents in the assay, and the techniques of the

individual performing the test. 2-6 Standard clarithromycin powder should provide the following range

of MIC values as noted in Table 12. For the diffusion technique using the 15 mcg disk, the criteria in

Table 12 should be achieved.

Table 12. Acceptable Quality Control Ranges for Clarithromycin

QC Strain MIC (mcg/mL) Zone diameter (mm)

Staphylococcus aureus ATCC 29213 a 0.12 – 0.5 --

Staphylococcus aureus ATCC 25923 -- 26 – 32

Streptococcus pneumoniae ATCC 49619 0.03 – 0.12 b 25 – 31 c

Haemophilus influenzae ATCC 49247 4 – 16 d 11 – 17 e

Helicobacter pylori ATCC 43504 0.015 – 0.12 f --

M. avium ATCC 700898 1 – 4 g --

a ATCC is a registered trademark of the American Type Culture Collection.

b This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution

procedure using cation adjusted Mueller Hinton broth with 2-5% lysed horse blood 2,3.

c This quality control range is applicable only to S. pneumoniae ATCC 49619 for tests performed by

disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood 3,4.

d This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution

procedure using HTM 2,3.

e This quality control limit applies to disk diffusion tests conducted with Haemophilus influenzae

ATCC 49247 using HTM 3,4.

f These are quality control ranges for the agar dilution methodology 6 and should not be used to control

test results obtained using alternative methods.

g When tested at pH 6.8 (if tested at pH 5.0 to 7.4 at 7.4, the acceptable range is 0.5 mcg/mL to 2

mcg/mL) 5.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The following in vitro mutagenicity tests have been conducted with clarithromycin:

Salmonella/Mammalian Microsomes 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 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.

Impairment of Fertility

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/ 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 twice the human serum levels.

Testicular atrophy occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8

times greater than the maximum human daily dose (on a body surface area basis).

13.2 Animal Toxicology and/or Pharmacology

Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the

maximum human daily dose (on a body surface area basis). Lymphoid depletion occurred in dogs at

doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose

(on a body surface area basis).

14.1 Mycobacterial Infections

Prophylaxis of Mycobacterial Infections

A randomized, double-blind clinical trial (trial 3) compared clarithromycin 500 mg twice a day to

placebo in patients with CDC-defined AIDS and CD 4 counts less than 100 cells/µL. This trial accrued

682 patients from November 1992 to January 1994, with a median CD 4 cell count at entry of 30

cells/mcL. Median duration of clarithromycin was 10.6 months vs. 8.2 months for placebo. More

patients in the placebo arm than the clarithromycin arm discontinued prematurely from the trial (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. The

trial was designed to evaluate the following endpoints:

MAC bacteremia, defined as at least one positive culture for Mycobacterium avium complex bacteria

from blood or another normally sterile site

Survival

Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or

symptoms of serious MAC infection, including fever, night sweats, weight loss, anemia, or elevations

in liver function tests

MAC Bacteremia

In patients randomized to clarithromycin, the risk of MAC bacteremia was reduced by 69% compared to

placebo. The difference between groups was statistically significant (p < 0.001). On an intent-to-treat

basis, the one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to

clarithromycin and 19.4% for patients randomized to placebo. 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 CD 4 count of 10 cells/mm 3 (range 2

cells/mm 3 to 25 cells/mm 3). 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 CD 4 count of 25 cells/mm 3 (range 10

cells/mm 3 to 80 cells/mm 3). Comparatively, 53 of the 341 placebo patients developed MAC; none of

these isolates were resistant to clarithromycin. The median baseline CD 4 count was 15 cells/mm 3

(range 2 cells/mm 3 to 130 cells/mm 3) for placebo patients that developed MAC.

Survival

A statistically significant survival benefit of clarithromycin compared to placebo was observed (see

Figure 3 and Table 13). Since the analysis at 18 months includes patients no longer receiving

prophylaxis the survival benefit of clarithromycin may be underestimated.

[survival-graph]

Figure 3. Survival of All Randomized AIDS Patients Over Time in Trial 3

Table 13. Mortality Rates at 18 months in Trial 3

Mortality Rates Reduction inMortality Rates on Clarithromycin

Placebo Clarithromycin

6 month 9.4% 6.5% 31%

12 month 29.7% 20.5% 31%

18 month 46.4% 37.5% 20%

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of MAC bacteremia, patients in the group randomized to

clarithromycin showed reductions in the signs and symptoms of disseminated MAC disease, including

fever, night sweats, weight loss, and anemia.

Treatment of Mycobacterial Infections

Dose-Ranging Monotherapy Trials in Adult AIDS Patients with MAC

Two randomized clinical trials (Trials 1 and 2) compared different dosages of clarithromycin in patients

with CDC-defined AIDS and CD 4 counts less than100 cells/mcL. These trials accrued patients from

May 1991 to March 1992. Trial 500 was a randomized, double-blind trial; trial 577 was an open-label

compassionate use trial. Both trials used 500 mg and 1000 mg twice daily dosing of clarithromycin;

trial 1 also had a 2000 mg twice daily clarithromycin group. Trial 1 enrolled 154 adult patients and trial

2 enrolled 469 adult patients. The majority of patients had CD 4 cell counts less than 50 cells/mcL at

study entry. The trials 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.

The results for trial 1 are described below. The trial 2 results were similar to the results of trial 1.

MAC Bacteremia

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all

clarithromycin dosage groups. The mean reductions in MAC colony forming units (CFU) from baseline

after 4 weeks of therapy in the 1000 mg (n=32) twice daily and 2000 mg (n=26) twice daily regimen was

2.3 Log CFU compared to 1.5 Log CFU in the clarithromycin 500 mg twice daily (n=35) regimen. A

separate trial with a four drug regimen 7 (ciprofloxacin, ethambutol, rifampicin, and clofazimine) had a

mean reduction of 1.4 Log CFU.

Clinical outcomes evaluated with the different dosing regimens of clarithromycin monotherapy are

shown in Table 14. The 1000 mg and 2000 mg twice daily doses showed significantly better control of

bacteremia during the first four weeks of therapy. No significant differences were seen beyond that

point. All of the isolates had MIC less than 8 mcg/mL at pre-treatment. Relapse was almost always

accompanied by an increase in MIC.

Table 14. Outcome with the Different Dosing Regimens of Clarithromycin

Outcome Clarithromycin 500 mg twice daily Clarithromycin 1000 mg twice daily Clarithromycin 2000

mg twice daily

One or more negative blood cultures at any time during acute therapy 61% (30/49) 59% (29/49) 52%

(25/48)

Two or more negative blood cultures during acute therapy sustained through study day 84 25% (12/49)

25% (12/49) 8% (4/48)

Death or discontinuation by day 84 23% (11/49) 37% (18/49) 56% (27/48)

Relapse by day 84 14% (7/49) 12% (6/49) 13% (6/48)

Median time to first negative culture (in days) 54 41 29

Median time to first decrease of at least 1 log CFU (in days) 29 16 15

Median time to first positive culture or study discontinuation following the first negative culture (in

days) 43 59 43

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 mg 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 15 below.

The median duration of response, defined as improvement or resolution of clinical signs and symptoms,

was 2 weeks to 6 weeks.

Since the trial 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.

Table 15. Response Rates for Clinical Signs of MAC During 6 Weeks to 12 Weeks of Treatment

Resolution of Fever Resolution of Night Sweats

Clarithromycin twice daily

dose (mg) % ever

afebrile % afebrile

6 weeks or more Clarithromycin twice daily

dose (mg) % ever

resolving % resolving

6 weeks or more

500 67% 23% 500 85% 42%

1000 67% 12% 1000 70% 33%

2000 62% 22% 2000 72% 36%

Weight Gain Greater Than 3% Hemoglobin Increase Greater Than 1 gm

Clarithromycin twice daily

dose (mg) % ever

gaining % gaining

6 weeks or more Clarithromycin twice daily

dose (mg) % ever

increasing % increasing

6 weeks or more

500 33% 14% 500 58% 26%

1000 26% 17% 1000 37% 6%

2000 26% 12% 2000 62% 18%

Survival

Median survival time from trial entry (trial 1) 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 two

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. 7

Median survival time from entry in trial 2 was 199 days for the 500 mg twice a day dose and 179 days

for the 1000 mg twice a day dose. During the first four 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.

Dosage-Ranging Monotherapy Trials in Pediatric AIDS Patients with MAC

Trial 4 was a pediatric trial of 3.75 mg/kg, 7.5 mg/kg, and 15 mg/kg of clarithromycin twice daily in

patients with CDC-defined AIDS and CD 4 counts less than 100 cells/mcL. The trial enrolled 25

patients between the ages of 1 to 20. The trial evaluated the same endpoints as in the adult trials 1 and 2.

Results with the 7.5 mg/kg twice daily dose in the pediatric trial were comparable to those for the 500

mg twice daily regimen in the adult trials.

Combination Therapy in AIDS Patients with Disseminated MAC

Trial 5 compared the safety and efficacy of clarithromycin in combination with ethambutol versus

clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC

(dMAC) infection. This 24-week trial enrolled 106 patients with AIDS and dMAC, with 55 patients

randomized to receive clarithromycin and ethambutol, and 51 patients randomized to receive

clarithromycin, ethambutol, and clofazime. Baseline characteristics between treatment arms were similar

with the exception of median CFU counts being at least 1 log higher in the clarithromycin, ethambutol,

and clofazime arm.

Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of

clarithromycin and ethambutol extended the time to microbiologic relapse, largely through suppressing

the emergence of clarithromycin resistant strains. However, the addition of clofazimine to the regimen

added no additional microbiologic or clinical benefit. Tolerability of both multidrug regimens was

comparable with the most common adverse events being gastrointestinal in nature. Patients receiving the

clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial

colony counts were higher. The results of this trial support the addition of ethambutol to clarithromycin

for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent.

14.2 Otitis Media

Otitis Media Trial of Clarithromycin vs. Oral Cephalosporin

In a controlled clinical trial of pediatric patients with 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 this trial, strict evaluability criteria were used to determine

clinical response. For the 223 patients who were evaluated for clinical efficacy, the clinical success

rate (i.e., cure plus improvement) at the post-therapy visit was 88% for clarithromycin and 91% for the

cephalosporin.

In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The

presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 16.

Table 16. Clinical Success Rates of Otitis Media Treatment by Pathogen

Pathogen Clinical Success Rates

Clarithromycin Oral Cephalosporin

S. pneumoniae 13/15 (87%) 4/5

H. influenzaea 10/14 (71%) 3/4

M. catarrhalis 4/5 1/1

S. pyogenes 3/3 0/1

All Pathogens Combined 30/37 (81%) 8/11 (73%)

a None of the H. influenzae isolated pre-treatment was resistant to clarithromycin; 6% were resistant to

the control agent.

Otitis Media Trials of Clarithromycin vs. Antimicrobial/Beta-lactamase Inhibitor

In two 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. In these trials, strict

evaluability criteria were used to determine the clinical responses. In the 233 patients who were

evaluated for clinical efficacy, the combined clinical success rate (i.e., cure and improvement) at the

post-therapy visit was 91% for both clarithromycin and the control.

For the patients who had microbiologic determinations at the pre-treatment visit, the presumptive

bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 17.

Table 17. Clinical Success Rates of Acute Otitis Media Treatment by Pathogen

Clinical Success Rates

PATHOGEN Clarithromycin Antimicrobial/Beta-lactamase Inhibitor

S. pneumoniae 43/51 (84%) 55/56 (98%)

H. influenzaea 36/45 (80%) 31/33 (94%)

M. catarrhalis 9/10 (90%) 6/6

S. pyogenes 3/3 5/5

All Pathogens Combined 91/109 (83%) 97/100 (97%)

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

resistant to the control agent.

14.3 H. pylori Eradication to Decrease the Risk of Duodenal Ulcer Recurrence

Clarithromycin + Lansoprazole and Amoxicillin

Two U.S. randomized, double-blind clinical trials (trial 6 and trial 7) in patients with H. pylori and

duodenal ulcer disease (defined as an active ulcer or history of an active ulcer within one year)

evaluated the efficacy of clarithromycin 500 mg twice daily in combination with lansoprazole 30 mg

twice daily and amoxicillin 1 gm twice daily as 14-day triple therapy for eradication of H. pylori.

H. pylori eradication was defined as two negative tests (culture and histology) at 4 weeks to 6 weeks

following the end of treatment.

The combination of clarithromycin plus lansoprazole and amoxicillin as triple therapy was effective in

eradication of H. pylori (see results in Table 18). Eradication of H. pylori has been shown to reduce the

risk of duodenal ulcer recurrence.

A randomized, double-blind clinical trial (trial 8) performed in the U.S. in patients with H. pylori and

duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the

efficacy of clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10

days and 14 days. This trial established that the 10-day triple therapy was equivalent to the 14-day triple

therapy in eradicating H. pylori (see results in Table 18).

Table 18. H. pylori Eradication Rates-Triple Therapy (clarithromycin/lansoprazole/amoxicillin)

Percent of Patients Cured [95% Confidence Interval] (number of patients)

Trial Duration Triple Therapy

Evaluable Analysis a Triple Therapy

Intent-to-Treat Analysis b

Trial 6 14 days 92 c [80-97.7]

(n = 48) 86 c [73.3-93.5]

(n = 55)

Trial 7 14 days 86 d [75.7-93.6]

(n = 66) 83 d [72-90.8]

(n = 70)

Trial 8 e 14 days 85 [77-91]

(N = 113) 82 [73.9-88.1]

(N = 126)

10 days 84 [76-89.8]

(N = 123) 81 [73.9-87.6]

(N = 135)

a Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori

infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta

West LTD., Bentley, Australia), histology, and/or culture. Patients were included in the analysis if they

completed the trial. Additionally, if patients were dropped out of the trial due to an adverse reaction

related to the drug, they were included in the analysis as evaluable failures of therapy.

b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined

above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as

failures of therapy.

c (p < 0.05) versus clarithromycin/lansoprazole and lansoprazole/amoxicillin dual therapy.

d (p < 0.05) versus clarithromycin/amoxicillin dual therapy.

e The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day, is (-10.5,

8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

Clarithromycin + Omeprazole and Amoxicillin Therapy

Three U.S., randomized, double-blind clinical trials in patients with H. pylori infection and duodenal

ulcer disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus

amoxicillin. Two trials (trials 9 and 10) were conducted in patients with an active duodenal ulcer, and

the third trial (trial 11) was conducted in patients with a duodenal ulcer in the past 5 years, but without an

ulcer present at the time of enrollment. The dosage regimen in the trials was clarithromycin 500 mg

twice a day plus omeprazole 20 mg twice a day plus amoxicillin 1 gram twice a day for 10 days. In trials

9 and 10, patients who took the omeprazole regimen also received an additional 18 days of omeprazole

20 mg once a day. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (trials 9

and 10 only). H. pylori status was determined by CLOtest ®, histology, and culture in all three trials.

For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and

none was positive. The combination of clarithromycin plus omeprazole and amoxicillin was effective in

eradicating H. pylori (see results in Table 19).

Table 19. H. pylori Eradication Rates: % of Patients Cured [95% Confidence Interval]

Clarithromycin + omeprazole + amoxicillin Clarithromycin + amoxicillin

Per-Protocol a Intent-to-Treat b Per-Protocol a Intent-to-Treat b

Trial 9 c77 [64, 86]

(n = 64) 69 [57, 79]

(n = 80) 43 [31, 56]

(n = 67) 37 [27, 48]

(n = 84)

Trial 10 c78 [67, 88]

(n = 65) 73 [61, 82]

(n = 77) 41 [29, 54]

(n = 68) 36 [26, 47]

(n = 84)

Trial 11 c90 [80, 96]

(n = 69) 83 [74, 91]

(n = 84) 33 [24, 44]

(n = 93) 32 [23, 42]

(n = 99)

a Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer trials

9 and 10; history of ulcer within 5 years, trial 11) and H. pylori infection at baseline defined as at least

two of three positive endoscopic tests from CLOtest ®, histology, and/or culture. Patients were

included in the analysis if they completed the trial. Additionally, if patients dropped out of the trial due

to an adverse reaction related to the study drug, they were included in the analysis as failures of

therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past

history of ulcer.

b Patients were included in the analysis if they had documented H. pylori infection at baseline and had

confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.

c p < 0.05 versus clarithromycin plus amoxicillin.

Clarithromycin + Omeprazole Therapy

Four randomized, double-blind, multi-center trials (trials 12, 13, 14, and 15) evaluated clarithromycin

500 mg three times a day plus omeprazole 40 mg once a day for 14 days, followed by omeprazole 20

mg once a day (trials 12, 13, and 15) or by omeprazole 40 mg once a day (trial 14) for an additional 14

days in patients with active duodenal ulcer associated with H. pylori. Trials 12 and 13 were conducted

in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal

ulcer were confirmed in 219 patients in trial 12 and 228 patients in trial 13. These trials compared the

combination regimen to omeprazole and clarithromycin monotherapies. Trials 14 and 15were conducted

in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were

confirmed in 148 patients in trial 14 and 208 patients in trial 15. These trials compared the combination

regimen to omeprazole monotherapy. The results for the efficacy analyses for these trials are

described in Tables 20, 21, and 22.

Duodenal Ulcer Healing

The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing

duodenal ulcer (see Table 20).

Table 20. End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (n/N)

Trial Clarithromycin + Omeprazole Omeprazole Clarithromycin

U.S. Trials

Trial 13 94% (58/62) a 88% (60/68) 71% (49/69)

Trial 12 88% (56/64) a 85% (55/65) 64% (44/69)

Non-U.S. Trials

Trial 15 99% (84/85) 95% (82/86) N/A

Trial 14 b 100% (64/64) 99% (71/72) N/A

a p < 0.05 for clarithromycin + omeprazole versus clarithromycin monotherapy.

b In trial 14 patients received omeprazole 40 mg daily for days 15 to 28.

Eradication of H. pylori Associated with Duodenal Ulcer

The combination of clarithromycin and omeprazole was effective in eradicating H. pylori (see Table

21). H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following

the end of treatment, and two negative tests were required to be considered eradicated. In the per-

protocol analysis, the following patients were excluded: dropouts, patients with major protocol

violations, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H.

pylori eradication at 4 weeks after the end of treatment because they were found to have an unhealed

ulcer at the end of treatment.

Table 21. H. pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured

(n/N)

Trial Clarithromycin + Omeprazole Omeprazole Clarithromycin

U.S. Trials

Trial 13 64% (39/61) a,b 0% (0/59) 39% (17/44)

Trial 12 74% (39/53) a,b 0% (0/54) 31% (13/42)

Non-U.S. Trials

Trial 15 74% (64/86) b 1% (1/90) N/A

Trial 14 83% (50/60) b 1% (1/74) N/A

a Statistically significantly higher than clarithromycin monotherapy (p < 0.05).

b Statistically significantly higher than omeprazole monotherapy (p < 0.05).

Duodenal Ulcer Recurrence

Ulcer recurrence at 6-months and at 12 months following the end of treatment was assessed for patients

in whom ulcers were healed post-treatment (see the results in Table 22). Thus, in patients with duodenal

ulcer associated with H. pylori infection, eradication of H. pylori reduced ulcer recurrence.

Table 22. Duodenal Ulcer Recurrence at 6 months and 12 months in Patients with Healed Ulcers

H. pylori Negative at 4-6 Weeks H. pylori Positive at 4-6 Weeks

U.S. Trials

Recurrence at 6 Months

Trial 100

Clarithromycin + Omeprazole 6% (2/34) 56% (9/16)

Omeprazole (0/0) 71% (35/49)

Clarithromycin 12% (2/17) 32% (7/22)

Trial 067

Clarithromycin + Omeprazole 38% (11/29) 50% (6/12)

Omeprazole (0/0) 67% (31/46)

Clarithromycin 18% (2/11) 52% (14/27)

Non-U.S. Trials

Recurrence at 6 Months

Trial 058

Clarithromycin + Omeprazole 6% (3/53) 24% (4/17)

Omeprazole 0% (0/3) 55% (39/71)

Trial 812b

Clarithromycin + Omeprazole 5% (2/42) 0% (0/7)

Omeprazole 0% (0/1) 54% (32/59)

Non-U.S. Trials

Recurrence at 12-Months in Trial 14

Clarithromycin + Omeprazole 3% (1/40) 0% (0/6)

Omeprazole 0% (0/1) 67% (29/43)

Winkel P, Hilden J, Hansen JF, Kastrup J, Kolmos HJ, Kjøller E, et al. Clarithromycin for stable

coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity

over 10 years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol 2015;182:459-65.

Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility

Tests for Bacteria that Grow Aerobically; Approved Standard—Tenth edition. CLSI Document M07-

A10, Clinical and Laboratory Standards Institute, 950 West Valley Rd, Suite 2500, Wayne, Pennsylvania

19087, USA, 2015.

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial

Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25, Clinical and

Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA,

2015.

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk

Diffusion Susceptibility Tests; Approved Standard—Twelfth Edition. CLSI document M02-A12,

Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania

19087, USA, 2015.

Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiae,

and Other Aerobic Actinomycetes; Approved Standard—Second Edition. CLSI document M24-A2,

Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania

19087, USA, 2011.

Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk

Susceptibility Testing for Infrequently Isolated or Fastidious Bacteria; Approved Guideline—Second

Edition. CLSI document M45-A2, Clinical and Laboratory Standards Institute, 950 West Valley Road,

Suite 2500, Wayne, Pennsylvania 19087, USA, 2010.

Kemper CA, et al. Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug

Oral Regimen. Ann Intern Med. 1992;116:466-472.

Clarithromycin Tablets, USP are supplied as white to off-white oval film-coated tablets in the

following packaging sizes:

250 mg tablets: (imprinted in blue with the “S39” on one side)

Bottles of 60

500 mg tablets: (debossed with the “S4” on one side)

Bottles of 60 mycin tablets, USP at controlled room temperature 20° to 25°C (68° to 77°F) in a well-

closed container.

Provide the following instructions or information about clarithromycin tablets to patients:

Counsel patients that antibacterial drugs including clarithromycin tablets should only be used to treat

bacterial infections. They do not treat viral infections (e.g., the common cold). When clarithromycin

tablet is prescribed to treat a bacterial infection, patients should be told that although it is common to

feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping

doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate

treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by

clarithromycin tablets or other antibacterial drugs in the future.

Advise patients that diarrhea is a common problem caused by antibacterials including clarithromycin

tablets which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with

antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and

fever) even as late as two or more months after having taken the last dose of the antibacterial. If this

occurs, instruct patients to contact their healthcare provider as soon as possible.

Advise patients that clarithromycin tablets may interact with some drugs; therefore, advise patients to

report to their healthcare provider the use of any other medications.

Advise patients that clarithromycin tablets can be taken with or without food and can be taken with milk.

There are no data on the effect of clarithromycin tablets on the ability to drive or use machines.

However, counsel patients regarding the potential for dizziness, vertigo, confusion and disorientation,

which may occur with the medication. The potential for these adverse reactions should be taken into

account before patients drive or use machines.

Advise patients that if pregnancy occurs while taking this drug, there is a potential hazard to the fetus

[see Warnings and Precautions (5.7)and Use in Specific Populations (8.1)] .

Advise patients who have coronary artery disease to continue medications and lifestyle modifications

for their coronary artery disease because clarithromycin tablets may be associated with increased risk

for mortality years after the end of clarithromycin tablets treatment.

* All trademark names are the property of their respective owners.

Manufactured by:

[logo] Sunshine Lake Pharma Co., Ltd.

Northern Industry Road 1#,

Song Shan Lake, DongGuan,

GuangDong Province, 523808,

P.R. China

Manufactured for:

Lannett Company, Inc.

Philadelphia, PA 19154

Rev. 10/17 10-307

3613

CLARITHROMYCIN

clarithromycin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -6 43(NDC:0 527-19 32)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CLARITHRO MYCIN (UNII: H1250 JIK0 A) (CLARITHROMYCIN - UNII:H1250 JIK0 A)

CLARITHROMYCIN

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)

CRO SCARMELLO SE SO DIUM (UNII: M28 OL1HH48 )

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Dire ct_Rx

Product Characteristics

Color

white

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -6 43-10

10 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /12/20 19

2

NDC:6 19 19 -6 43-20

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

11/0 6 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 358 4

0 8 /12/20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(6 19 19 -6 43)

Revised: 11/2019

Similar products

Search alerts related to this product

View documents history

Share this information