CLARITHROMYCIN

KAISER FOUNDATION HOSPITALS

FULL PRESCRIBING INFORMATION: CONTENTS*

• CLARITHROMYCIN DESCRIPTION
• CLINICAL PHARMACOLOGY
• MICROBIOLOGY
• CLARITHROMYCIN INDICATIONS AND USAGE
• CLARITHROMYCIN CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• Information For Patients
• Drug Interactions
• Carcinogenesis, Mutagenesis, Impairment of Fertility
• Pregnancy
• Nursing Mothers
• Geriatric Use
• CLARITHROMYCIN ADVERSE REACTIONS
• OVERDOSAGE
• CLARITHROMYCIN DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• CLINICAL STUDIES
• ANIMAL PHARMACOLOGY AND TOXICOLOGY
• REFERENCES

FULL PRESCRIBING INFORMATION

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 bacteria.

CLARITHROMYCIN DESCRIPTION

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C₃₈H₆₉NO₁₃, and the molecular weight is 747.96. The structural formula is:

CLINICAL PHARMACOLOGY

Pharmacokinetics

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The
absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500mg 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 antimicrobially 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, USP may be given without regard to food.

In nonfasting healthy human subjects (males and females), peak plasma concentrations were
attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 μg/mL with a 250 mg dose administered every 12 hours and 3 to 4 μg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 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 μg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 μg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 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 (125mg/5mL) 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.

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 or 1000mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 μg/mL and 5 to 10 μg/mL, respectively.

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

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

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.

BIAXIN XL Filmtab (clarithromycin extended-release tablets) provide extended absorption of
clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal total daily dose of immediate-release clarithromycin tablets, BIAXIN XL tablets provide lower and later steadystate peak plasma concentrations but equivalent 24-hour AUC's for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of formation of 14-OH clarithromycin following administration of BIAXIN XL tablets (2 × 500 mg once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Therefore, BIAXIN XL tablets should be taken with food.

Steady-State Clarithromycin Plasma Concentration-Time Profiles

In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 to 3 μg/mL were achieved about 5 to 8 hours after oral administration of 2 × 500mg BIAXIN XL tablets once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.8 μg/mL were attained about 6 to 9 hours after dosing. Steady-state peak plasma clarithromycin concentrations of approximately 1 to 2 μg/mL were achieved about 5 to 6 hours after oral administration of a single 500 mg BIAXIN XL tablet once daily; for 14-OH clarithromycin, steadystate peak plasma concentrations of approximately 0.6μg/mL were attained about 6 hours after dosing.

When 250 mg doses of Clarithromycin for Oral Suspension, USP were administered to fasting healthy adult subjects, peak plasma concentrations were attained around 3 hours after dosing. Steady-state peak plasma concentrations were attained in 2 to 3 days and were approximately 2μg/mL for clarithromycin and 0.7 μg/mL for 14-OH clarithromycin when 250 mg doses of the clarithromycin suspension were administered every 12 hours. Elimination half-life of clarithromycin (3 to 4 hours) and that of 14-OH clarithromycin (5 to 7 hours) were similar to those observed at steady state following administration of equivalent doses of Clarithromycin Tablets, USP.

For adult patients, the bioavailability of 10 mL of the 125mg/5 mL suspension or 10 mL of the 250mg/5 mL suspension is similar to a 250 mg or 500 mg tablet, respectively.

In children requiring antibiotic therapy, administration of 7.5 mg/kg q12h doses of clarithromycin as
the suspension generally resulted in steady-state peak plasma concentrations of 3 to 7 μg/mL for
clarithromycin and 1 to 2 μg/mL for 14-OH clarithromycin.

In HIV-infected children taking 15 mg/kg every 12 hours, steady-state clarithromycin peak
concentrations generally ranged from 6 to 15 μg/mL.

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

In adults given 250 mg clarithromycin as suspension (n = 22), food appeared to decrease mean peak plasma clarithromycin concentrations from 1.2 (± 0.4) μg/mL to 1.0 (± 0.4) μg/mL and the extent of absorption from 7.2 (± 2.5) hr• μg/mL to 6.5 (± 3.7) hr• μg/mL.

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

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to
healthy adult males. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were
increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

For information about other drugs indicated in combination with clarithromycin, refer to the CLINICAL PHARMACOLOGY section of their package inserts.

MICROBIOLOGY

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

Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms.

Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown.

Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

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 procedure. Standardized procedures are based on a dilution method¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. The MIC values should be interpreted according to the following criteria:

CLARITHROMYCIN INDICATIONS AND USAGE

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP are indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions as listed below:

Adults (Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP)

Pharyngitis/Tonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not available at present).

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae , Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR).

Uncomplicated skin and skin structure infections due to Staphylococcus aureus , or Streptococcus pyogenes (Abscesses usually require surgical drainage).

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 or TRITEC
(ranitidine bismuth citrate) tablets are also indicated for the treatment of patients with an active
duodenal ulcer associated with H. pylori infection. However, regimens which contain clarithromycin as
the single antimicrobial 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.

In patients who fail therapy, susceptibility testing should be done if possible. If resistance to
clarithromycin is demonstrated, a non-clarithromycin-containing therapy is recommended. (For
information on development of resistance see Microbiology section.) The eradication of H. pylori has
been demonstrated to reduce the risk of duodenal ulcer recurrence.

Children (Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP)

Pharyngitis/Tonsillitis due to Streptococcus pyogenes

Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae, or
Chlamydia pneumoniae (TWAR)

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus
pneumoniae

Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis,or Streptococcus
pneumoniae

NOTE: For information on otitis media, see CLINICAL STUDIES - Otitis Media.

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus
pyogenes (Abscesses usually require surgical drainage.)

Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare

Adults (BIAXIN XL Filmtab Tablets)

BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions listed below:

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Community-Acquired Pneumonia due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Streptococcus pneumoniae, Chlamydia pneumoniae (TWAR), or Mycoplasma pneumoniae

THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN ESTABLISHED.

Prophylaxis

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP are indicated for the
prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced
HIV infection.

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.

CLARITHROMYCIN CONTRAINDICATIONS

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin,
erythromycin, or any of the macrolide antibiotics.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated:
cisapride, pimozide, astemizole, terfenadine and ergotamine or dihydroergotamine (See Drug
Interactions). There have been post-marketing reports of drug interactions when clarithromycin and/or
erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine 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 erythromycin and clarithromycin.
Fatalities have been reported.

For information about contraindications of other drugs indicated in combination with clarithromycin,
refer to the CONTRAINDICATIONS section of their package inserts.

WARNINGS

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. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN
MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM
RECOMMENDED HUMAN DOSES. (See PRECAUTIONS - Pregnancy .)

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 antibiotic 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 antibiotic use not directed against C. difficile may need to
be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic
treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin
and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency.
Deaths have been reported in some such patients. (See PRECAUTIONS.)

For information about warnings of other drugs indicated in combination with clarithromycin, refer to
the WARNINGS section of their package inserts.

PRECAUTIONS

General

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.

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.

Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients
with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION.)

Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a
history of acute porphyria.

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic
syndrome has been reported in patients receiving clarithromycin therapy.

For information about precautions of other drugs indicated in combination with clarithromycin, refer to
the PRECAUTIONS section of their package inserts.

Information For Patients

Patients should be counseled that antibacterial drugs including clarithromycin should only be used to
treat bacterial infections. They do not treat viral infections (e.g., the common cold). When
clarithromycin 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 or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is
discontinued. Sometimes after starting treatment with antibiotics, 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 antibiotic. If this occurs, patients should contact their physician as
soon as possible.

Clarithromycin may interact with some drugs; therefore patients should be advised to report to their
doctor the use of any other medications.

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP can be taken with or
without food and can be taken with milk; however, BIAXIN XL (clarithromycin extended-release
tablets) should be taken with food. Do NOT refrigerate the suspension.

Drug Interactions

Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. 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%.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving
concurrent verapamil, belonging to the calcium channel blockers drug class.

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.

When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid
metabolite of terfenadine were threefold higher, on average, than the values observed when
terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not significantly affected by coadministration of terfenadine once clarithromycin
reached steady-state conditions. Concomitant administration of clarithromycin with terfenadine is
contraindicated. (See CONTRAINDICATIONS.)

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 t_½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of
clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered
alone and 5.7 when coadministered with clarithromycin.

Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant.

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult
patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin
appears to interfere with absorption of simultaneously administered oral zidovudine, this interaction
can be largely avoided by staggering the doses of clarithromycin and zidovudine. This interaction
does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with
zidovudine or dideoxyinosine. Similar interaction studies have not been conducted with clarithromycin
extended release and zidovudine.

Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients
resulted in no statistically significant change in didanosine pharmacokinetics.

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21
healthy volunteers led to increases in the mean steady-state clarithromycin C_min and AUC of 33% and
18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affected
by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

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. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CL_CR 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CL_CR less than 30 mL/min, the dose of clarithromycin should be decreased by 75%.

Spontaneous reports in the post-marketing 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.

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is
known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by
clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in
patients receiving clarithromycin and digoxin concomitantly have also been reported in postmarketing
surveillance. Some patients have shown clinical signs consistent with digoxin toxicity,
including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored
while patients are receiving digoxin and clarithromycin simultaneously.

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. When clarithromycin and
colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to
increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine
toxicity. (See WARNINGS.)

Co-administration of clarithromycin, 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. Dosage adjustments
may be considered, and when possible, serum concentrations of drugs primarily metabolized by
CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following are examples of some clinically significant CYP3A based drug interactions. Interactions
with other drugs metabolized by the CYP3A isoform are also possible.

Carbamazepine and Terfenadine

Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were
observed in clinical trials with clarithromycin.

Efavirenz, Nevirapine, Rifampicin, Rifabutin and Rifapentine

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine,
rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower
the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that
is also microbiologically active. 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.

Sildenafil, Tadalafil, and Vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A
may be inhibited by concomitantly administered clarithromycin.

Coadministration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased
phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should
be considered when these drugs are co-administered with clarithromycin.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (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. A reduction in tolterodine dosage may be necessary in the presence of
CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam
AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral
administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If
intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored
to allow dose adjustment.

The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A,
including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for
their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with
clarithromycin is unlikely. There have been post-marketing 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.

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a
bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir
(400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in
exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir.

Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary
in patients with normal renal function. For patients with moderate renal function (creatinine clearance
30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with
creatinine clearance less than 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should
not be coadministered with protease inhibitors.

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional
drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while
itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and
clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or
prolonged pharmacologic effects.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a
bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg bid) and
saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state AUC
and C_max values of saquinavir which were 177% and 187% higher than those seen with saquinavir
alone. Clarithromycin AUC and C_max values were approximately 40% higher than those seen with
clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a
limited time at the doses/formulations studied. Observations from drug interaction studies using the
soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir
hard gelatin capsule. Observations from drug interactions studies performed with saquinavir alone
may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is
co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on
clarithromycin (see PRECAUTIONS – Drug Interactions).

The following CYP3A based drug interactions have been observed with erythromycin products and/or
with clarithromycin in post-marketing experience:

Antiarrhythmics

There have been post-marketing 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. Serum concentrations of
these medications should also be monitored.

Ergotamine/Dihydroergotamine

Post-marketing 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. Concomitant
administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated (see
CONTRAINDICATIONS).

Triazolobenziodidiazepines (Such as Triazolam and Alprazolam) and Related Benzodiazepines (Such as Midazolam)

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus,
may increase the pharmacologic effect of these benzodiazepines. There have been post-marketing
reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant
use of clarithromycin and triazolam.

HMG-CoA Reductase Inhibitors

As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA
reductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been
reported in patients taking these drugs concomitantly.

Sildenafil (Viagra)

Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. A similar
interaction may occur with clarithromycin; reduction of sildenafil dosage should be considered. (See
Viagra package insert.)

There have been spontaneous or published reports of CYP3A based interactions of erythromycin
and/or clarithromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide,
rifabutin, quinidine, methylprednisolone, cilostazol, bromocriptine and vinblastine.

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine is
contraindicated (see CONTRAINDICATIONS.)

In addition, there have been reports of interactions of erythromycin or clarithromycin with drugs not
thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.

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 weakly
positive in one test and negative in another.

In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin
metabolites with negative results.

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the
recommended maximum human dose based on mg/m²) to male and female rats caused no adverse
effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in
rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When
given orally at 150 mg/kg/day (2.4 times the recommended maximum human dose based on mg/m²),
clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to
marked maternal toxicity of the drug at this high dose.

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

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

Pregnancy

Teratogenic Effects

Nursing Mothers

It is not known whether clarithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clarithromycin is administered to a nursing woman. It is known that clarithromycin is excreted in the milk of lactating animals and that other drugs of this class are excreted in human milk. Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.

PEDIATRIC USE

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. Neonatal and juvenile animals tolerated clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes but were less sensitive to toxicity in the liver, kidney, thymus, and genitalia.

Geriatric Use

In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg 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 events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. (See WARNINGS and PRECAUTIONS.)

CLARITHROMYCIN ADVERSE REACTIONS

The majority of side effects observed in clinical trials were of a mild and transient nature. Fewer than
3% of adult patients without mycobacterial infections and fewer than 2% of pediatric patients without
mycobacterial infections discontinued therapy because of drug-related side effects. Fewer than 2% of
adult patients taking BIAXIN XL tablets discontinued therapy because of drug-related side effects.

The most frequently reported events in adults taking Clarithromycin Tablets, USP were diarrhea (3%),
nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache
(2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%),
abdominal pain (3%), rash (3%), and headache (2%). Most of these events were described as mild or
moderate in severity. Of the reported adverse events, only 1% was described as severe.

The most frequently reported events in adults taking BIAXIN XL (clarithromycin extended-release
tablets) were diarrhea (6%), abnormal taste (7%), and nausea (3%). Most of these events were
described as mild or moderate in severity. Of the reported adverse events, less than 1% were
described as severe.

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall
gastrointestinal adverse events were reported by a similar proportion of patients taking either
Clarithromycin Tablets, USP or BIAXIN XL tablets; however, patients taking BIAXIN XL tablets
reported significantly less severe gastrointestinal symptoms compared to patients taking
Clarithromycin Tablets, USP. In addition, patients taking BIAXIN XL tablets had significantly fewer
premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events
compared to Clarithromycin Tablets, USP.

In community-acquired pneumonia studies conducted in adults comparing clarithromycin to
erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive
system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs. 32%;
p less than 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse
events compared to 4% of clarithromycin-treated patients.

In two U.S. studies of acute otitis media comparing clarithromycin to amoxicillin/potassium
clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in
clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21%
vs. 40%, p less than 0.001). One-third as many clarithromycin-treated patients reported diarrhea as did
amoxicillin/potassium clavulanate-treated patients.

Post-Marketing Experience

Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis,
Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred. Other spontaneously
reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis,
tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been
reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually
reversible with professional dental cleaning. There have been isolated reports of hearing loss, which
is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell
including smell loss, usually in conjunction with taste perversion or taste loss, have also been
reported.

Transient CNS events including anxiety, behavioral changes, confusional states, convulsions,
depersonalization, disorientation, hallucinations, insomnia, depression, manic behavior, nightmares,
psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance.
Events usually resolve with discontinuation of the drug.

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic
hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic
dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal
outcome has been reported and generally has been associated with serious underlying diseases
and/or concomitant medications.

There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral
hypoglycemic agents or insulin.

There have been post-marketing reports of BIAXIN XL 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.

As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular
arrhythmias, including ventricular tachycardia and torsades de pointes.

There have been reports of interstitial nephritis coincident with clarithromycin use.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin
and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency.
Deaths have been reported in some such patients. (See WARNINGS and PRECAUTIONS.)

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance were as follows:

Hepatic

Elevated SGPT (ALT) less than 1%; SGOT (AST) less than 1%; GGT less than 1%; alkaline phosphatase less than 1%; LDH less than 1%; total bilirubin less than 1%

Hematologic

Decreased WBC less than 1%; elevated prothrombin time 1%

Renal

Elevated BUN 4%; elevated serum creatinine less than 1%

GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.

OVERDOSAGE

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain,
vomiting, nausea, and diarrhea.

Adverse reactions accompanying overdosage should be treated 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 DOSAGE AND ADMINISTRATION

Clarithromycin Tablets, USP and Clarithromycin for Oral Suspension, USP may be given with or
without food. BIAXIN XL Filmtab (clarithromycin extended-release tablets) should be taken with food.
BIAXIN XL tablets should be swallowed whole and not chewed, broken or crushed.

HOW SUPPLIED

Clarithromycin Tablets, USP are supplied as yellow oval film-coated tablets in the following packaging
sizes:

500 mg tablets: (debossed with DV on one side, and D on the opposite side)

Bottles of 720 (NDC 0179-0021-88)

Store 500 mg Clarithromycin Tablets, USP at controlled room temperature 20° to 25°C (68° to 77°F)
in a well-closed container.

CLINICAL STUDIES

Mycobacterial Infections

Prophylaxis

A randomized, double-blind study (561) compared clarithromycin 500 mg b.i.d. to placebo in patients
with CDC-defined AIDS and CD₄ counts less than 100 cells/μL. This study accrued 682 patients from
November 1992 to January 1994, with a median CD₄ cell count at study entry of 30 cells/μL. 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 study (75.6% and 67.4%,
respectively). However, if premature discontinuations due to 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 study was designed to evaluate the
following endpoints:

• MAC bacteremia, defined as at least one positive culture for M. 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.

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 less than 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 CD₄ count of 10 cells/mm³ (range 2 to 25 cells/mm³). Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited. The 8 patients who received clarithromycin and developed susceptible MAC bacteremia had a median baseline CD₄ count of 25 cells/mm³ (range 10 to 80 cells/mm³). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to clarithromycin. The median baseline CD₄ count was 15 cells/mm³ (range 2 to 130 cells/mm³) for placebo patients that developed MAC.

Survival
A statistically significant survival benefit was observed.

Survival All Randomized Patients

	Mortality
	Placebo	Clarithromycin	Reduction in Mortality on Clarithromycin
6 month	9.4%	6.5%	31%
12 month	29.7%	20.5%	31%
18 month	46.4%	37.5%	20%

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

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of 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.

Safety

In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M.
avium, it was often difficult to distinguish adverse events 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.

Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated group compared to the placebo-treated group.

Discontinuation due to adverse events was required 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 of Potential Clinical Importance

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.

Treatment

Three randomized studies (500, 577, and 521) compared different dosages of clarithromycin in patients with CDC-defined AIDS and CD₄ counts less than 100 cells/µL. These studies accrued patients from May 1991 to March 1992. Study 500 was randomized, double-blind; Study 577 was open-label compassionate use. Both studies used 500 and 1000 mg b.i.d. doses; Study 500 also had a 2000 mg b.i.d. group. Study 521 was a pediatric study at 3.75, 7.5, and 15 mg/kg b.i.d. Study 500 enrolled 154 adult patients, Study 577 enrolled 469 adult patients, and Study 521 enrolled 25 patients between the ages of 1 to 20. The majority of patients had CD₄ cell counts less than 50/µL at study entry. The studies were designed to evaluate the following end points:

1. Change in MAC bacteremia or blood cultures negative for M. avium.

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

Study 069 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.⁴ This 24-week study 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 clofazimine. Baseline characteristics between study arms were similar with the exception of median CFU counts being at least 1 log higher in the clarithromycin, ethambutol, and clofazimine arm.

Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol was well tolerated and 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.

MAC Bacteremia

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all
dose groups. Mean reductions in colony forming units (CFU) are shown below. Included in the table
are results from a separate study with a four drug regimen⁵ (ciprofloxacin, ethambutol, rifampicin, and
clofazimine). Since patient populations and study procedures may vary between these two studies,
comparisons between the clarithromycin results and the combination therapy results should be
interpreted cautiously.

Although the 1000 mg and 2000 mg b.i.d. doses showed significantly better control of bacteremia during the first four weeks of therapy, no significant differences were seen beyond that point. The percent of patients whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was 61% (30/49) for the 500 mg b.i.d. group and 59% (29/49) and 52% (25/48) for the 1000 and 2000 mg b.i.d. groups, respectively. The percent of patients who had 2 or more negative cultures during acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg b.i.d. groups and 8% (4/48) for the 2000 mg b.i.d. group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49), and 13% (6/48) of patients had relapsed in the 500, 1000, and 2000 mg b.i.d. dose groups, respectively. All of the isolates had an MIC less than 8 µg/mL at pre-treatment. Relapse was almost always accompanied by an increase in MIC. The median time to first negative culture was 54, 41, and 29 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively. The time to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg b.i.d. doses (median equal to 16 and 15 days, respectively) in comparison to the 500 mg b.i.d. group (median equal to 29 days). The median time to first positive culture or study discontinuation following the first negative culture was 43, 59 and 43 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively.

Clinically Significant Disseminated MAC Disease

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

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

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

Survival

Median survival time from study entry (Study 500) was 249 days at the 500 mg b.i.d. dose compared
to 215 days with the 1000 mg b.i.d. dose. However, during the first 12 weeks of therapy, there were 2
deaths in 53 patients in the 500 mg b.i.d. group versus 13 deaths in 51 patients in the 1000 mg b.i.d.
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.⁵

Median survival time from study entry in Study 577 was 199 days for the 500 mg b.i.d. dose and 179
days for the 1000 mg b.i.d. 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
b.i.d. and 18 deaths in 214 patients taking 1000 mg b.i.d.

Safety

The adverse event profiles showed that both the 500 and 1000 mg b.i.d. doses were well tolerated.
The 2000 mg b.i.d. dose was poorly tolerated and resulted in a higher proportion of premature
discontinuations.

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 events possibly associated with clarithromycin administration from underlying signs of HIV
disease or intercurrent illness.

The following analyses summarize experience during the first 12 weeks of therapy with
clarithromycin. Data are reported separately for Study 500 (randomized, double-blind) and Study 577
(open-label, compassionate use) and also combined. Adverse events were reported less frequently in
Study 577, which may be due in part to differences in monitoring between the two studies. In adult
patients receiving clarithromycin 500 mg b.i.d., the most frequently reported adverse events,
considered possibly or probably related to study drug, with an incidence of 5% or greater, are listed
below. Most of these events were mild to moderate in severity, although 5% (Study 500: 8%; Study
577: 4%) of patients receiving 500 mg b.i.d. and 5% (Study 500: 4%; Study 577: 6%) of patients
receiving 1000 mg b.i.d. reported severe adverse events. Excluding those patients who discontinued
therapy or died due to complications of their underlying non-mycobacterial disease, approximately 8%
(Study 500: 15%; Study 577: 7%) of the patients who received 500 mg b.i.d. and 12% (Study 500:
14%; Study 577: 12%) of the patients who received 1000 mg b.i.d. discontinued therapy due to drugrelated events during the first 12 weeks of therapy. Overall, the 500 and 1000 mg b.i.d. doses had
similar adverse event profiles.

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 studies, very 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.

Duodenal Ulcer Associated with H. pylori Infection

Clarithromycin + Lansoprazole and Amoxicillin

H. pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence

Two U.S. randomized, double-blind clinical studies 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 in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy
for eradication of H. pylori . Based on the results of these studies, the safety and efficacy of the
following eradication regimen were established:

Triple therapy: clarithromycin 500 mg b.i.d. + lansoprazole 30 mg b.i.d. + amoxicillin 1 gm b.i.d.

Treatment was for 14 days. H. pylori eradication was defined as two negative tests (culture and
histology) at 4 to 6 weeks following the end of treatment.

The combination of clarithromycin plus lansoprazole and amoxicillin as triple therapy was effective in
eradicating H. pylori . Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer
recurrence.

A randomized, double-blind clinical study 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
and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple
therapy in eradicating H. pylori .

#   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.

†  (p less than 0.05) versus BIAXIN/lansoprazole and lansoprazole/amoxicillin dual therapy.

‡   (p less than 0.05) versus BIAXIN/amoxicillin dual therapy.

¶   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.

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole were as follows:

Hepatic - elevated direct bilirubin less than 1%; GGT less than 1%; SGOT (AST) less than 1%; SGPT (ALT) less than 1%.

Renal - elevated serum creatinine less than 1%.

For information on omeprazole, refer to the ADVERSE REACTIONS section of the PRILOSEC package insert.

ANIMAL PHARMACOLOGY AND TOXICOLOGY

Clarithromycin is rapidly and well-absorbed with dose-linear kinetics, low protein binding, and a high volume of distribution. Plasma half-life ranged from 1 to 6 hours and was species dependent. High tissue concentrations were achieved, but negligible accumulation was observed. Fecal clearance predominated. Hepatotoxicity occurred in all species tested (i.e., in rats and monkeys at doses 2 times greater than and in dogs at doses comparable to the maximum human daily dose, based on mg/m²). Renal tubular degeneration (calculated on a mg/m² basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose. Testicular atrophy (on a mg/m² basis) 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. Corneal opacity (on a mg/m² basis) occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose. Lymphoid depletion (on a mg/m² basis) occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose. These adverse events were absent during clinical trials.

REFERENCES

• National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.
• National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.
• National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL. January 11-13, 1998.
• Chaisson RE, et al. Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection. AIDS. 1997;11:311-317.
• 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.