Biaxin

BIAXIN BID (clarithromycin tablets, USP, film-coated) and BIAXIN (clarithromycin for oral suspension, USP) may be given with or without meals. BIAXIN XL (clarithromycin extended-release tablets) must be taken with food.

For more information on drug interactions for omeprazole and amoxicillin, refer to their respective Product Monographs, under Drug Interactions.

Bi-directional drug interactions are complex and may occur if both of the interacting drugs are substrates and inhibitors/ inducers of CYP3A.

Interactions with laboratory tests have not been established.

Clarithromycin is an inhibitor of CYP3A and P-gp. This inhibition may lead to increased or prolonged serum levels of those drugs also metabolized by CYP3A or transported by P-gp when co-administered with clarithromycin. For such drugs the monitoring of their serum concentrations may be necessary.

Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A and/or P-gp substrates, especially if the CYP3A/P-gp substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by CYP3A or transported by P-gp. Dosage adjustments may be considered, and when possible, serum concentrations of these drugs should be monitored closely in patients concurrently receiving clarithromycin.

With certain drugs, co-administration of clarithromycin should be avoided, e.g. oral midazolam (see Table 14).

Interactions with herbal products have not been established.

Clarithromycin is a substrate of CYP3A. Co-administration of strong inducers of the cytochrome P450 metabolism system may accelerate the metabolism of clarithromycin and thus lower exposure to clarithromycin while increasing exposure to its metabolite 14-OH-clarithromycin which could impair the intended therapeutic effect. Co-administration of potent CYP3A inhibitors may lead to increased exposure to clarithromycin and decreased exposure to its metabolite 14-OH-clarithromycin. Clarithromycin dosage adjustment or consideration of alternative treatments may be required.

Many categories of drugs are metabolized by CYP3A and/or transported by P-gp located in the liver and in the intestine. Some drugs may inhibit or induce the activities of CYP3A and/or P-gp. Administration of such inhibitors or inducers may impact upon the metabolism. In some cases serum concentrations may be increased and in others decreased. Care must therefore be exercised when co-administering such drugs.

Interactions with clarithromycin have been reported with drugs metabolized by cytochrome P450 isoforms other than CYP3A system. Additional mechanisms, such as effects upon absorption, may also be responsible for interaction between drugs, including zidovudine and clarithromycin.

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to MAC. Clarithromycin should be used in combination with other antimycobacterial drugs which have shown in vitro activity against MAC, including ethambutol and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC.

The recommended dose for mycobacterial infections in adults is 500 mg b.i.d.

Treatment of disseminated MAC infections in AIDS patients should continue for life if clinical and mycobacterial improvement are observed.

BIAXIN BID may be taken with or without food.

BIAXIN XL (clarithromycin extended-release tablets ) must be taken with food. The tablets should be swallowed whole and not chewed, broken or crushed.

BIAXIN (clarithromycin for oral suspension, USP) may be taken with or without food.

Based on studies done with BIAXIN BID, no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function.

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to MAC. Clarithromycin should be used in combination with other antimycobacterial drugs which have shown in vitro activity against MAC, including ethambutol and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC.

In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. clarithromycin per day in two divided doses. Dosing recommendations for children are shown in Table 17.

Treatment of disseminated MAC infections in AIDS patients should continue for life if clinical and mycobacterial improvement are observed.

Based on a study done with BIAXIN BID, patients with severe renal impairment (CR_CL <30 mL/min) have greater clarithromycin exposure than patients with normal renal function (CR_CL ≥80 mL/min). Clarithromycin C_max was about 3.3 times higher and AUC was about 4.2 times higher in the patients with severe renal impairment. The maximum daily clarithromycin dose for patients with severe renal impairment is 500 mg. The safety and efficacy of 500 mg clarithromycin in patients with severe renal impairment has not been established.

In the same study, patients with moderate renal impairment (CR_CL 30-79 mL/min) had greater clarithromycin exposure than patients with normal renal function, but the elevations were much less than those observed in severe renal impairment. Compared to the subjects with normal renal function, the clarithromycin C_max was about 52% higher and the AUC was about 74% higher in the patients with moderate renal impairment. No clarithromycin dose adjustment is required for patients with moderate renal impairment.

79 mL of water should be added to the granules in the bottle and shaken to yield 150 mL of reconstituted suspension.

54 mL of water should be added to the granules in the bottle and shaken to yield 105 mL of reconstituted suspension.

Shake well before use. The reconstituted suspension must not be refrigerated. Any reconstituted unused medication should be discarded after 14 days. The graduated syringe included in the package should be rinsed between uses. Do not leave syringe in bottle. Do not store reconstituted suspension in syringe.

If a dose of clarithromycin is missed, the patient should take the dose as soon as possible and then return to their normal scheduled dose. However, if a dose is skipped, the patient should not double the next dose.

The recommended dose of BIAXIN BID for the prevention of disseminated M. avium disease is 500 mg b.i.d.

29 mL of water should be added to the granules in the bottle and shaken to yield 55 mL of reconstituted suspension.

In patients who are sensitive to penicillin-based therapy (e.g. amoxicillin), dual therapy with clarithromycin and omeprazole may provide a feasible alternative.

The recommended dose is clarithromycin 500 mg t.i.d plus omeprazole 40 mg q.d. for 14 days, followed by 20 mg omeprazole q.d. for 14 days.

Optimal therapeutic regimens consisting of a shorter treatment duration for the eradication of H. pylori are yet to be determined.

BIAXIN BID (clarithromycin tablets, USP, film-coated) and BIAXIN (clarithromycin for oral suspension, USP) may be given with or without meals. BIAXIN XL (clarithromycin extended-release tablets) must be taken with food.

In patients with both hepatic and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate (see Dosage and Administration, Recommended Dose and Dosage Adjustment).

In children with renal impairment and a creatinine clearance less than 30 mL/min, the dosage of BIAXIN should be reduced by one-half, i.e., up to 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

The recommended dose is clarithromycin 500 mg b.i.d. in conjunction with amoxicillin 1 g b.i.d. and omeprazole 20 mg daily for 10 days.

For more information on omeprazole or amoxicillin, refer to their respective Product Monographs, under Dosage and Administration.

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

In the treatment of Group A streptococcus infections, therapy should be continued for 10 days. The usual drug of choice in the treatment of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the i.m 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 presently available.

Abnormal Hematologic and Clinical Chemistry Findings in Patients with Respiratory Tract or Skin Infections Treated with BIAXIN BID

x

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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, General and Drug Interactions, Drug-Drug Interactions).

In studies of adults with pneumonia comparing clarithromycin to erythromycin base or erythromycin stearate, there were significantly fewer adverse events involving the digestive system in patients treated with clarithromycin.

Number of Pediatric AIDS Patients Treated with Clarithromycin for Mycobacterial Infections who had On-Treatment Laboratory Values that Were Outside the Seriously Abnormal Level

x

The majority of the patients reported adverse event in the Gastrointestinal disorders system organ class (SOC) (19%), and the Infections and infestations SOC (9%).

The events occurring most frequently in the Gastrointestinal disorder SOC were diarrhea (7%), vomiting (7%), abdominal pain (3%), dyspepsia (3%) and nausea (1%).

Other adverse events included infection (3%), rhinitis (2.2%), rash (2.2%), increased cough (2.1%), fever (2.2%), headache (1.6%), conjunctivitis (1.1%), dysgeusia(3%) and transient elevation of AST (0.9%).

The majority of adverse events were considered by the investigators to have either mild or moderate severity. 375/1829 patients (21%) had a mild adverse events, 175/1829 patients (10%) had moderate adverse events and 20/1829 patients (1%) had severe adverse events.

In the two U.S. acute otitis media studies of clarithromycin versus antimicrobial/beta-lactamase inhibitor, the incidence of adverse events in all patients treated, primarily diarrhea (15% vs. 38%) and diaper rash (3% vs.11%) in young children, was clinically or statistically lower in the clarithromycin arm versus the control arm.

In another U.S. otitis media study of clarithromycin versus cephalosporin, the incidence of adverse events in all patients treated, primarily diarrhea and vomiting, did not differ clinically or statistically for the two agents.

Fewer than 2% of adult patients taking BIAXIN XL (clarithromycin extended-release tablets) discontinued therapy because of drug-related side effects. The most frequently reported adverse events in adults taking 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.

There have been rare 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.

(Other adverse reactions have been observed in different patient populations and during post-marketing surveillance. Please also refer to Adverse Reactions, Clinical Trial Adverse Drug Reactions, Patients with Respiratory Tract or Skin Infections.)

In patients with acquired immune deficiency syndrome (AIDS) and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for prevention or treatment of mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness. Other adverse reactions have been observed in different patient populations and during post-marketing surveillance. Please also refer to Adverse Reactions, Clinical Trial Adverse Drug Reactions, Patients with Respiratory Tract or Skin Infections.

The majority of side effects observed in clinical trials involving 3563 patients treated with BIAXIN BID were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side-effects. The most common drug-related adverse reactions in adults taking BIAXIN BID were nausea, diarrhea, abdominal pain, dyspepsia, headache, taste perversion and vomiting. In pediatric patients taking BIAXIN (oral suspension), the most frequently reported events were diarrhea, vomiting, abdominal pain, dyspepsia, taste perversion and infection. The most frequently reported events in adults taking BIAXIN XL were diarrhea, abnormal taste and nausea.

Twelve (4%) of the clarithromycin/omeprazole-treated patients prematurely discontinued from study drug therapy due to adverse events. The most frequently reported adverse events leading to withdrawal included taste perversion, nausea, and headache. Three patients treated with clarithromycin and omeprazole died during follow-up periods; none of the deaths were considered by the investigator to be related to study drug administration.

Few laboratory abnormalities were observed among clarithromycin/ omeprazole-treated patients. The incidence of possibly clinically significant hematology and serum chemistry variables was <1% for any variable evaluated.

Dosing recommendations for children are based on body weight. Please see Dosage and Administration, Table 17 for determining dosage. For a brief discussion please see Warnings and Precautions, Special Populations, Pediatrics (6 months-12 years of age).

Dosage adjustment should be considered in elderly patients with severe renal impairment. For a brief discussion please see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age).

BIAXIN XL (clarithromycin extended-release tablets) may be indicated in the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the diseases listed below:

Pharyngitis caused by S. pyogenes (Group A β-hemolytic streptococci).

Acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae.

Mild to moderate community-acquired pneumonia caused by S. pneumoniae, C. pneumoniae, or M. pneumoniae.

Disseminated mycobacterial infections due to M. avium and M. intracellulare.

BIAXIN BID (clarithromycin tablets, USP, film-coated) in the presence of acid suppression (with omeprazole) with another antibiotic (amoxicillin) is indicated for the eradication of H. pylori that may result in decreased recurrence of duodenal ulcer in patients with active duodenal ulcers and who are H. pylori positive.

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

BIAXIN (clarithromycin for oral suspension, USP) is indicated for the treatment of infections due to susceptible organisms, in the following conditions:

BIAXIN BID (clarithromycin tablets, USP, film-coated) may be indicated in the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the diseases listed below:

Uncomplicated skin and skin structure infections (i.e., impetigo and cellulitis) caused by S. aureus or S. pyogenes.

Each oval, debossed, yellow, film-coated, extended-release tablet contains: clarithromycin 500 mg. Nonmedicinal ingredients: cellulosic polymers, lactose monohydrate, magnesium stearate, propylene glycol, Quinoline Yellow Lake E104, sorbitan monooleate, talc, titanium dioxide and vanillin. Tartrazine-free. HDPE bottles of 60. Also available in 7-Day Treatment PAC (14 tablets) and 10-Day Treatment PAC (20 tablets).

Each oval, printed with Abbott logo on one side, yellow, film-coated tablet contains: clarithromycin 250 mg. Nonmedicinal ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. Tartrazine-free. HDPE bottles of 100 and 250.

Each oval, printed with Abbott logo on one side, pale yellow, film-coated tablet contains: clarithromycin 500 mg. Nonmedicinal ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. Tartrazine-free. HDPE bottles of 100.

HDPE bottle which allows capacity for shaking consists of a: granulation of clarithromycin with carbopol and povidone (K90) which is coated with HP-55 polymer (hydroxypropylmethylcellulose phthalate). Nonmedicinal ingredients: castor oil, citric acid, flavor (artificial and natural fruit), maltodextrin, potassium sorbate, silicon dioxide, sucrose, titanium dioxide and xanthan gum. Water is added to reconstitute the suspension prior to use. When reconstituted, the concentration of clarithromycin is 125 mg/5 mL or 250 mg/5 mL. HDPE bottles of 55, 105 and 150 mL (125 mg/5 mL) and 105 mL (250 mg/5 mL). A graduated syringe is included in the package.

Clarithromycin is principally excreted by the liver and kidney. In patients with both hepatic and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate (see Dosage and Administration, Recommended Dose and Dosage Adjustment).

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

Clarithromycin is principally excreted by the liver and kidney. In patients with both hepatic and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate (see Dosage and Administration, Recommended Dose and Dosage Adjustment).

Dosage adjustment should be considered in elderly patients with severe renal impairment. 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 concentrations of clarithromycin and 14-OH clarithromycin were increased. The AUC was also increased. 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.

Use of clarithromycin tablets in children under 12 years of age has not been studied.

Use of clarithromycin for oral suspension, USP in children under 6 months has not been studied. In pneumonia, clarithromycin granules were not studied in children younger than 3 years.

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.

Increased valproate and phenobarbital concentrations and extreme sedation were noted in a 3-year old patient coincident with clarithromycin therapy. Cause and effect relationship cannot be established. However, monitoring of valproate and phenobarbital concentrations may be considered.

C. difficile-Associated Disease: C. difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including clarithromycin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over two months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against C. difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile. Surgical evaluation should be instituted as clinically indicated; as surgical intervention may be required in certain severe cases (see Adverse Reactions).

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

The following in vitro mutagenicity tests have been conducted with clarithromycin: Salmonella/mammalian microsome test, bacterial induced mutation frequency test, in vitro chromosome aberration test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal study, mouse micronucleus test. All tests had negative results except the in vitro chromosome aberration test which was weakly positive in one test and negative in another. In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Clarithromycin should be administered with caution to any patient who has demonstrated some form of drug allergy, particularly to structurally related-drugs. If an allergic reaction to clarithromycin occurs, administration of the drug should be discontinued. Serious hypersensitivity reactions may require epinephrine, antihistamines, or corticosteroids.

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.

There have been post-marketing reports of colchicine toxicity with concurrent use of clarithromycin and colchicine. In patients with impaired renal function and/or who are elderly, colchicine and clarithromycin should not be used concurrently due to the risk of colchicine toxicity. Deaths have been reported in some such patients (see Drug Interactions, Drug-Drug Interactions, Colchicine and Adverse Reactions, Post-Market Adverse Drug Reactions).

Several studies of HIV-positive patients receiving clarithromycin for treatment of MAC infection have shown poorer survival in those patients randomized to receive doses higher than 500 mg b.i.d. The explanation for the poorer survival associated with doses higher than 500 mg b.i.d. has not been determined. Treatment or prophylaxis of MAC infection with clarithromycin should not exceed the approved dose of 500 mg b.i.d.

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

Use of clarithromycin with other drugs may lead to drug-drug interactions. For established or potential drug-drug interactions and their mechanisms, see Contraindications and Drug Interactions, Drug-Drug Interactions.

Triple and Dual Therapy with Omeprazole. Among the 113 triple therapy recipients with pretreatment H. pylori isolates susceptible to clarithromycin, 2/102 patients (2%) developed resistance after treatment with omeprazole, clarithromycin, and amoxicillin. Among patients who received triple therapy, 6/108 (5.6%) patients had pretreatment H. pylori isolates resistant to clarithromycin. Of these 6 patients, 3 (50%) had H. pylori eradicated at follow-up, and 3 (50%) remained positive after treatment. In 5/113 (4.4%) patients, no susceptibility data for clarithromycin pretreatment were available. Twenty-six patients 26/104 (25%) with pretreatment isolates susceptible to clarithromycin developed resistance after treatment with omeprazole and clarithromycin. Development of clarithromycin resistance should be considered as a possible risk especially when less efficient treatment regimens are used.

The development of resistance (11 out of 19 breakthrough isolates in one study) has been seen in HIV positive patients receiving clarithromycin for prophylaxis and treatment of MAC infection.

To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.

There are no adequate and well-controlled studies in pregnant women. The benefits against risk, particularly during the first 3 months of pregnancy should be carefully weighed by a physician (see Warnings and Precautions, Serious Warnings and Precautions). 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 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 2 times the human serum levels.

Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day 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 2 times the human serum levels.

Embryonic loss has been seen in monkeys and rabbits.

The safety of clarithromycin for use during breast feeding of infants has not been established. Clarithromycin is 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.

Store extended-release tablets between 15 and 25°C in a tightly closed container. Protect from light.

Store film-coated tablets between 15 and 25°C in a tightly closed container. Protect from light.

Store granules for suspension between 15 and 25°C in a tightly closed bottle. Protect from light. The reconstituted suspension must not be refrigerated. Any reconstituted unused medication should be discarded after 14 days. The graduated syringe included in the package should be rinsed between uses. Do not leave syringe in bottle. Do not store reconstituted suspension in syringe.

Representative Clarithromycin Tissue and Serum Concentrations Following the Administration of 250 mg b.i.d of Clarithromycin Film-Coated Tablets

At 250 mg twice daily, approximately 20% of an orally administered dose of clarithromycin film-coated tablet is excreted in the urine as the unchanged parent drug. The urinary excretion of unchanged clarithromycin is somewhat greater (approximately 30%) with 500 mg twice daily dosing. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH-clarithromycin which accounts for an additional 10 to 15% of the dose with twice daily dosing at either 250 mg or 500 mg. Most of the remainder of the dose is eliminated in the feces, primarily via the bile. About 5-10% of the parent drug is recovered from the feces. Fecal metabolites are largely products of N-demethylation, 14-hydroxylation or both.

Clarithromycin is principally excreted by the liver and kidney. The major metabolite found in urine is 14-OH-clarithromycin.

The absolute bioavailability of 250 mg and 500 mg clarithromycin tablets is approximately 50%. Food slightly delays the onset of clarithromycin absorption but does not affect the extent of bioavailability. Therefore, BIAXIN BID tablets may be given without regard to meals.

In fasting healthy human subjects, peak serum concentrations are attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations, which are attained within 2 to 3 days, are approximately 1 mg/L with a 250 mg dose twice daily and 2 to 3 mg/L with a 500 mg dose twice daily. The elimination half-life of clarithromycin is about 3 to 4 hours with 250 mg twice daily dosing but increases to about 5 to 7 hours with 500 mg administered twice daily.

Clarithromycin displays non-linear pharmacokinetics at clinically relevant doses, producing greater than proportional increases in AUC with increasing dose. The degree of non-linearity is reduced on chronic clarithromycin administration (i.e., at steady state). The non-linearity of the pharmacokinetics of the principle metabolite, 14-OH clarithromycin, is slight at the recommended doses of 250 mg and 500 mg administered twice daily. With 250 mg twice daily, 14-OH clarithromycin attains a peak steady state concentration of about 0.6 mg/L and has an elimination half-life of 5 to 6 hours. With a 500 mg twice daily dose, the peak steady-state of 14-OH concentrations of clarithromycin are slightly higher (up to 1 mg/L) and its elimination half-life is about 7 hours. With either dose, the steady-state concentration of this metabolite is generally attained within 2 to 3 days.

Adult Patients with HIV. Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin twice a day to adult patients with HIV infection were similar to those observed in healthy volunteers. However, at the higher clarithromycin doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at 500 mg clarithromycin doses. In adult HIV-infected patients taking 2000 mg/day in two divided doses, steady-state clarithromycin C_max values ranged from 5 to10 mg/L. C_max values as high as 27 mg/L have been observed in HIV-infected adult patients taking 4000 mg/day in two divided doses of clarithromycin tablets.

Elimination half-lives appeared to be lengthened at these higher doses as well. The higher clarithromycin concentrations and longer elimination half-lives observed at these doses are consistent with the known non-linearity in clarithromycin pharmacokinetics.

Clarithromycin and omeprazole. Clarithromycin 500 mg t.i.d. and omeprazole 40 mg q.d. were studied in fasting healthy adult subjects. When clarithromycin was given alone as 500 mg q8h, the mean steady state C_max value was approximately 3.8 µg/mL and the mean C_min value was approximately 1.8 µg/mL. The mean AUC_0-8 for clarithromycin was 22.9 µg·hr/mL. The T_max and half life were 2.1 hrs and 5.3 hrs, respectively, when clarithromycin was dosed at 500 mg t.i.d. When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC_0-24 were observed. For all subjects combined, the mean omeprazole AUC_0-24 was 89% greater and the harmonic mean for omeprazole t_½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C_max, C_min, and AUC_0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

Refer to Absorption.

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 subjects with impaired hepatic function when compared to healthy subjects (see Warnings and Precautions, Hepatic/Biliary/Pancreatic and Dosage and Administration, Recommended Dose and Dosage Adjustment).

Dosage adjustment should be considered in elderly with severe renal impairment. In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg of clarithromycin every 12 hours, the maximum concentrations of clarithromycin and 14-OH clarithromycin were increased. The AUC was also increased. 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.

Adult Volunteers. Single and multiple dose adult volunteer studies showed that the suspension formulation was not significantly different from the tablet formulation in terms of C_max of clarithromycin and AUC, although the onset and/or rate of absorption of the suspension formulation was slower than that of the tablet. As with the tablet formulation, steady state is achieved by the fifth dose of a 12 hour multiple-dose suspension regimen.

Children. In children taking 15 to 30 mg/kg/day in two divided doses, steady-state clarithromycin C_max values generally ranged from 8 to 20 µg/mL. C_max values as high as 23 µg/mL have been observed in HIV-infected pediatric patients taking 30 mg/kg/day in two divided doses. 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 A single and multiple dose study conducted in pediatric patients showed that food leads to a slight delay in the onset of absorption, but does not affect the overall bioavailability of clarithromycin.

Clarithromycin and its 14-OH metabolite penetrate into middle ear effusion (MEE) of patients with secretory otitis media.

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

Single dose adult volunteer studies show that the reformulated (125 mg/5 mL and 250 mg/5 mL) and the current (125 mg/5 mL) clarithromycin for oral suspension have comparable bioavailability under fasting and non-fasting conditions.

Clarithromycin extended-release tablets provided extended absorption of clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal dose of immediate-release clarithromycin film-coated tablets, clarithromycin extended-release tablets provide lower and later steady-state peak plasma concentrations, but equivalent 24-hour AUCs for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin.

While the extent of formation of 14-OH clarithromycin following administration of clarithromycin extended-release tablets (2×500 mg once daily) under steady-state conditions is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Similarly, single-dose administration of clarithromycin extended-release (500 mg once daily) is associated with a 25% lower clarithromycin AUC relative to administration of clarithromycin immediate-release film-coated tablets (250 mg b.i.d.). Therefore, it is recommended that BIAXIN XL (clarithromycin extended-release tablets be given with food.

Figure 1 illustrates the steady-state clarithromycin plasma concentration-time profile for BIAXIN XL (2×500 mg once daily) relative to BIAXIN (500 mg twice daily).

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria and suppressing protein synthesis.

The elimination of clarithromycin was impaired in patients with impaired renal function. The daily dose of clarithromycin should be limited to 500 mg in patients with severe renal impairment (CR_CL <30 mL/min) (see Warnings and Precautions, Renal and Dosage and Administration, Recommended Dose and Dosage Adjustment).

H. pylori is now established as a major etiological factor in duodenal ulcer disease. The presence of H. pylori may damage the mucosal integrity due to the production of enzymes (catalase, lipases, phospholipases, proteases, and urease), adhesins and toxins; the generated inflammatory response contributes to mucosal damage.

The concomitant administration of an antimicrobial(s) such as clarithromycin and an antisecretory agent, improves the eradication of H. pylori as compared to individual drug administration. The higher pH resulting from antisecretory treatment, optimizes the environment for the pharmacologic action of the antimicrobial agent(s) against H. pylori.

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