Pharmacology: Pharmacodynamics: Mechanism of Action: Clariget OD: Clarithromycin binds to the 50S ribosomal subunit of susceptible microorganisms and inhibits the translocation step resulting in inhibition of protein synthesis. The minimum inhibitory concentrations (MICs) of clarithromycin are generally 2-fold lower than the MICs of erythromycin. The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. 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.
Pharmacokinetics: Absorption: Clariget: Clarithromycin is rapidly absorbed from the GI tract after oral administration and the bioavailability of the parent drug is about 55%. Food slightly delays the absorption of clarithromycin but does not affect the extent of bioavailability, therefore it may be given without regard to food. Peak concentrations of clarithromycin and its principal active metabolite 14-hydroxyclarithromycin are reported to be about 0.6 and 0.7 mcg/mL, respectively, following a single 250-mg dose by mouth; at steady-state, the same dose given every 12 hrs as tablets produces peak concentrations of clarithromycin of about 1 mcg/mL. The same dose given as a suspension produces a steady-state plasma concentration of about 2 mcg/mL. The time to peak concentration is about 2-3 hrs.
The pharmacokinetics of clarithromycin is nonlinear and dose dependent; high doses may produce disproportionate increases in peak concentration of the parent drug, due to saturation of the metabolic pathways.
Clariget OD: Clarithromycin extended-release tablets provide extended absorption of clarithromycin from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 50%. Steady-state peak plasma concentrations of approximately 1-2 mcg/mL were achieved about 5-6 hrs after oral administration of a single clarithromycin 500 mg extended-release tablet once daily. For 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.6 mcg/mL were attained about 6 hrs after dosing. Little or no unpredicted accumulation was found and the metabolic disposition did not change following multiple dosing.
Effect of Food: Clariget OD: The extent of formation of 14-OH clarithromycin following administration of clarithromycin extended-release tablets (2 x 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, clarithromycin extended-release tablets should be taken with food.
Distribution: Clarithromycin and its principal metabolite are widely distributed and tissue concentrations exceed those in serum, in part because of intracellular uptake.
Clariget: Volume of distribution is 243-266 L.
Clariget OD: The protein binding of clarithromycin in human plasma averaged about 70%.
Metabolism and Excretion: Clariget: It is extensively metabolized in the liver and excreted in feces via the bile. Substantial amounts are excreted in urine; at steady-state, about 20 and 30% of a 250- or 500-mg dose, respectively, is excreted in this way as unchanged drug. 14-Hydroxyclarithromycin as well as other metabolites are also excreted in the urine accounting for 10-15% of the dose. The terminal t½ of clarithromycin is reportedly about 3-4 hrs in patients receiving 250-mg doses twice daily and about 5-7 hrs in those receiving 500 mg twice daily.
The principal metabolite, 14-OH-clarithromycin, has an elimination t½ of 5-6 hrs after a dose of 250 mg every 12 hrs. With a dose of 500 mg every 12 hrs, its elimination t½ is about 7 hrs. With either dose, the steady-state concentration of this metabolite is generally attained within 2-3 days.
Clariget OD: It is extensively metabolized in the liver and undergoes first-pass metabolism. Elimination half-lives of the parent drug and metabolite were approximately 5.3 hrs and 7.7 hrs, respectively. Urinary excretion accounts for approximately 40% of the clarithromycin dose. Fecal elimination accounts for approximately 30%. The apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at higher doses.
Special Populations: Clariget: Hepatic Impairment: The steady-state concentrations of clarithromycin in patients with impaired hepatic function did not differ from those of normal subjects; however, the 14-OH-clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH-clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.
Renal Impairment: The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function who received multiple 500-mg oral doses. The plasma levels, t½, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and the AUC was larger in subjects with renal impairment than its normal subjects. The extent to which these parameters differed was correlated with the degree of renal impairment; the more severe the renal impairment, the more significant the difference.
Elderly Subjects: In a comparative study of healthy, young adults and healthy, elderly subjects given multiple 500-mg oral doses of clarithromycin, the circulating plasma levels were higher and elimination was slower in the elderly group compared to the younger group. However, there was no difference between the 2 groups when renal clearance of clarithromycin was correlated with creatinine clearance. It was concluded from these results that any effect on the handling of clarithromycin is related to renal function and not subject to age.
Patients with Mycobacterial Infections: Steady-state concentrations of clarithromycin and 14-OH-clarithromycin observed following administration of usual doses to patients with HIV infections were similar to those observed in normal subjects. However, at the higher doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at usual doses. In children with HIV infection taking clarithromycin 15-30 mg/kg/day in 2 divided doses, steady-state Cmax values generally ranged from 8-20 mcg/mL. However, Cmax values as high as 23 mcg/mL have been observed in HIV-infected pediatric patients taking 30 mg/kg/day in 2 divided doses as clarithromycin pediatric suspension. Elimination half-lives appeared to be lengthened at these higher doses as compared to that observed with usual doses in normal subjects. The higher plasma concentrations and longer elimination half-lives observed at these doses are consistent with the known nonlinearity in clarithromycin pharmacokinetics.
Microbiology: Clariget: Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunits of susceptible bacteria and suppresses protein synthesis.
Clarithromycin has demonstrated excellent in vitro activity against both standard strains of bacteria and clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally 1 log2 dilution more potent than the MICs of erythromycin.
Clarithromycin is reported to be more active than erythromycin against susceptible streptococci and staphylococci in vitro as well as against some other species including Moraxella catarrhalis (Branhamella catarrhalis), Legionella spp, Chlamydia trachomatis and Ureaplasma urealyticum. Clarithromycin is reported to be more active than erythromycin or azithromycin against some mycobacteria including Mycobacterium avium complex and against M. leprae. It is reported to have some in vitro activity against the protozoan Toxoplasma gondii and may have some activity against cryptosporidia. The major metabolite 14-hydroxyclarithromycin is also active, and may enhance the activity of clarithromycin in vivo, notably against Haemophilus influenzae.
In vitro data also indicates that clarithromycin has excellent activity against Legionella pneumophila and Mycoplasma pneumoniae. It is bactericidal to Helicobacter pylori; this activity of clarithromycin is greater at neutral pH than at acid pH. In vitro and in vivo data show that this antibiotic has activity against clinically significant mycobacterial species.
Clariget OD: Clarithromycin has shown to be active against the following microorganisms: Aerobic Gram-positive Microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic Gram-negative Microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella spp (eg, Legionella pneumophila).
Anaerobes: Clostridium perfringens, Peptococcus sp, Peptostreptococcus sp, Propionibacterium acnes.
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, MAC (consisting of Mycobacterium avium, Mycobacterium intracellulare).
Other Microorganisms: Mycoplasma pneumoniae, Chlamydia pneumonia (TWAR), Chlamydia trachomatis, Ureaplasma urealyticum.