Klaricid/Klaricid OD

Klaricid/Klaricid OD Mechanism of Action

clarithromycin

Manufacturer:

Abbott

Distributor:

Abbott
Full Prescribing Info
Action
Pharmacotherapeutic group: Antibacterial for systemic use, macrolide. ATC-Code: J01FA09.
Pharmacology: Pharmacodynamics: Clarithromycin is a semi-synthetic macrolide antibiotic obtained by substitution of a CH3O group for the hydroxyl (OH) group at position 6 of the erythromycin lactonic ring. Specifically clarithromycin is 6-O-methyl erythromycin A. The white to off-white antibiotic powder is bitter, practically odorless, essentially insoluble in water, and slightly soluble in ethanol, methanol, and acetonitrile. Its molecular weight is 747.96.
Clinical Studies: Klaricid: Helicobacter pylori is strongly associated with peptic ulcer disease. Ninety (90) to 100% of patients with duodenal ulcers are infected with this pathogen. Eradication of H. pylori has been shown to reduce the rate of duodenal ulcer recurrence, thereby reducing the need for maintenance anti-secretory therapy.
Triple Therapy in Duodenal Ulcer: Disease In a well-controlled double blind study, H. pylori infected duodenal ulcer patients received triple therapy with clarithromycin 500 mg b.i.d., amoxicillin 1000 mg b.i.d. and omeprazole 20 mg daily for ten days or dual therapy with clarithromycin 500 mg t.i.d. and omeprazole 40 mg daily for 14 days. H. pylori was eradicated in 90% of the patients receiving clarithromycin triple therapy and in 60% of the patients receiving dual therapy.
In an independent study H. pylori infected patients received eradication therapy with clarithromycin 500 mg b.i.d. in conjunction with amoxicillin 1000 mg b.i.d. and omeprazole 20 mg daily (Group A) or omeprazole 20 mg b.i.d. (Group B) for seven days. In those patients not previously treated with anti-H. pylori therapy, H. pylori was eradicated in 86% (95% CI=69-95) of patients in Group A and 75% (95% CI=62-85) of patients in Group B, the difference was not statistically significant.
In an open-label study H. pylori infected patients with duodenal ulcer or non ulcer dyspepsia (NUD) received eradication therapy with clarithromycin 500 mg b.i.d., lansoprazole 30 mg b.i.d. plus amoxicillin 1000 mg b.i.d. for ten days. In an all-patients-treated analysis, H. pylori was eradicated from 91% of patients.
Dual Therapy in Duodenal Ulcer Disease: In well controlled, double-blind studies, H. pylori infected duodenal ulcer patients received eradication therapy with clarithromycin 500 mg t.i.d. and omeprazole 40 mg daily for 14 days followed by omeprazole 40 mg (study A) or omeprazole 20 mg (studies B, C and D) daily for an additional 14 days; patients in each control group received omeprazole alone for 28 days. In study A, H. pylori was eradicated in over 80% of patients who received clarithromycin and omeprazole and in only 1% of patients receiving omeprazole alone. In studies B, C, and D, the combined eradication rate was over 70% (clinically evaluable analysis) in patients receiving clarithromycin and omeprazole and less than 1% in patients receiving omeprazole alone. In each study, the rate of ulcer recurrence at six months was statistically lower in the clarithromycin and omeprazole treated patients when compared to patients receiving omeprazole alone.
In an investigator-blind study, H. pylori infected patients received eradication therapy with clarithromycin 500 mg t.i.d. in conjunction with lansoprazole 60 mg/day in single or divided doses for 14 days. The combined eradication rate was over 60%.
Klaricid Pediatric: Clinical Experience in Patients with Non-Mycobacterial Infections: In clinical studies, clarithromycin at a dose of 7.5 mg/kg b.i.d. was demonstrated to be safe and effective in the treatment of pediatric patients with infections requiring oral antibiotic treatment. It has been evaluated in over 1200 children, ages six months to 12 years, with otitis media, pharyngitis, skin infections and lower respiratory tract infections.
In these studies, clarithromycin at a dose of 7.5 mg/kg b.i.d. showed comparable clinical and bacteriological efficacy to the reference agents which included penicillin V, amoxicillin, amoxicillin/clavulanate, erythromycin ethylsuccinate, cefaclor and cefadroxil.
Clinical Experience in Patients with Mycobacterial Infections: A preliminary study in pediatric patients (some were HIV positive) with mycobacterial infections demonstrated that clarithromycin was a safe and effective treatment when given alone and in combination with zidovudine or dideoxyinosine. Clarithromycin Pediatric Suspension was administered as 7.5, 15 or 30 mg/kg/day in two divided doses.
Some statistically significant effects on pharmacokinetic parameters were observed when clarithromycin was administered with antiretroviral compounds; however, these changes were minor and not likely to be of clinical significance. Clarithromycin at doses of up to 30 mg/kg/day was well-tolerated.
Clarithromycin was effective in the treatment of disseminated M. avium complex infections in pediatric patients with AIDS, with some patients demonstrating continued efficacy after more than one year of therapy.
Pharmacokinetics: Klaricid: Absorption: The kinetics of orally administered clarithromycin has been studied extensively in a number of animal species and adult humans. These studies have shown clarithromycin is readily and rapidly absorbed with an absolute bioavailability of approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing. Food intake immediately before dosing increases clarithromycin bioavailability by a mean of 25%. Overall, this increase is minor and should be of little clinical significance with the recommended dosing regimens. Clarithromycin may thus be administered in either the presence or absence of food.
Distribution, Biotransformation and Elimination: In vitro: In vitro studies showed the protein binding of clarithromycin in human plasma averaged about 70% at concentrations of 0.45 to 4.5 μg/ml. A decrease in binding to 41% at 45.0 μg/ml suggested the binding sites might become saturated, but this only occurred at concentrations far in excess of the therapeutic drug levels.
In vivo: Results of animal studies showed clarithromycin levels in all tissues, except the central nervous system, were several times higher than the circulating drug levels. The highest concentrations were usually found in the liver and lung where the tissue to plasma (T/P) ratios reached 10 to 20.
Normal Subjects: With b.i.d. dosing at 250 mg, the peak steady state plasma concentration was attained in two to three days and averaged about 1 μg/ml for clarithromycin and 0.6 μg/ml for 14-OH- clarithromycin, while the elimination half-lives of the parent drug and metabolite were three to four hours and five to six hours, respectively. With b.i.d. dosing at 500 mg, the steady state Cmax for clarithromycin and its hydroxylated metabolite was achieved by the fifth dose. After the fifth and seventh doses, the steady state Cmax for clarithromycin averaged 2.7 and 2.9 μg/ml; its hydroxylated metabolite averaged 0.88 and 0.83 μg/ml, respectively. The half-life of the parent drug at the 500 mg dose level was 4.5 to 4.8 hours, while that of the 14-OH-clarithromycin was 6.9 to 8.7 hours. At steady state the 14-OH- clarithromycin levels did not increase proportionately with the clarithromycin dose, and the apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at the higher doses. This non-linear pharmacokinetic behavior of clarithromycin, coupled with the overall decrease in the formation of 14-hydroxylation and N-demethylation products at the higher doses, indicates the non-linear metabolism of clarithromycin becomes more pronounced at high doses.
In human adults given single oral doses of 250 mg or 1200 mg clarithromycin, urinary excretion accounted for 37.9% of the lower dose and 46.0% of the higher dose. Fecal elimination accounted for 40.2% and 29.1% (this included a subject with only one stool sample containing 14.1%) of these respective doses.
Patients: Clarithromycin and its 14-OH metabolite distribute readily into body tissues and fluids. Limited data from a small number of patients suggests clarithromycin does not achieve significant levels in cerebrospinal fluid after oral doses (i.e., only 1 to 2% of serum levels in CSF in patients with normal blood-CSF barriers). Concentrations in tissues are usually several fold higher than serum concentrations. Examples from tissue and serum concentrations are presented in Table 1. (See Table 1.)

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Hepatic Impairment: In a study comparing one group of healthy human subjects with a group of subjects with liver impairment who were given 250 mg of clarithromycin b.i.d. for two days and a single 250 mg dose the third day, steady state plasma levels and systemic clearing of clarithromycin were not significantly different between the two groups. In contrast, steady state concentrations of the 14-OH metabolite were markedly lower in the group of hepatic-impaired subjects. This decreased metabolic clearance of the parent compound by 14-hydroxylation was partially offset by an increase in the renal clearance of parent drug, resulting in comparable steady state levels of parent drug in the hepatic impaired and healthy subjects. These results indicate no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function.
Renal Impairment: A study was conducted to evaluate and compare the pharmacokinetic profile of multiple 500 mg oral doses of clarithromycin in subjects with normal and decreased renal function. The plasma levels, half- life, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and AUC was larger in subjects with renal impairment. Kelim and urinary excretion were lower. 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 (see Dosage & Administration).
Elderly Subjects: A study was also conducted to evaluate and compare the safety and pharmacokinetic profiles of multiple 500 mg oral doses of clarithromycin in healthy elderly male and female subjects to those in healthy young adult male subjects. In the elderly group, circulating plasma levels were higher and elimination slower than in the younger group for both parent drug and 14-OH metabolite. However, there was no difference between the two groups when renal clearance was correlated with creatinine clearance. It is concluded from those results that any effect on the handling of clarithromycin is related to renal function and not to age per se.
Mycobacterium avium Infections: 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 normal subjects. However, at the higher doses which may be required to treat Mycobacterium avium infections, clarithromycin concentrations were much higher than those observed at the usual doses. In adult HIV-infected patients taking 1000 and 2000 mg/day in two divided doses, steady-state clarithromycin Cmax values ranged from 2 to 4 μg/ml and 5 to 10 μg/ml, respectively. Elimination half-lives appeared to be lengthened at these higher doses as compared to that seen 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.
Concomitant Omeprazole Administration: A pharmacokinetic study was conducted with clarithromycin 500 mg t.i.d. and omeprazole 40 mg once daily. When clarithromycin was given alone at 500 mg every eight hours, the mean steady-state Cmax value was approximately 3.8 μg/ml and the mean Cmin value was approximately 1.8 μg/ml. The mean AUC0-8 for clarithromycin was 22.9 μg/hr/ml. The Tmax and half-life were 2.1 hr and 5.3 hr, respectively, when clarithromycin was dosed at 500 mg t.i.d.
In the same study when clarithromycin 500 mg t.i.d. was administered with omeprazole 40 mg once- daily, increases in omeprazole half-life and AUC0-24 were observed. For all subjects combined, the mean omeprazole AUC0-24 was 89% greater and the harmonic mean for omeprazole T½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state Cmax, Cmin, and AUC0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively, over values achieved when clarithromycin was administered with placebo.
At steady state, clarithromycin gastric mucous concentrations six hours post-dosing were approximately 25-fold higher in the clarithromycin/omeprazole group compared with the clarithromycin alone group. Six hours post-dosing, mean clarithromycin gastric tissue concentrations were approximately 2-fold higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo.
Klaricid OD: Absorption: The kinetics of orally administered clarithromycin (Klaricid OD) has been studied in adult humans and compared with clarithromycin 250 mg and 500 mg immediate release tablets. The extent of absorption was found to be equivalent when equal daily doses were administered. The absolute bioavailability is approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in humans following multiple dosing. Based upon the finding of equivalent extent of absorption, the following in vitro and in vivo data is applicable to the modified release formulation.
Distribution, Biotransformation and Elimination: In vitro: In vitro studies showed the protein binding of clarithromycin in human plasma averaged about 70% at concentrations of 0.45 to 4.5 μg/ml. A decrease in binding to 41% at 45.0 μg/ml suggested the binding sites might become saturated, but this only occurred at concentrations far in excess of the therapeutic drug levels.
In vivo: Results of animal studies showed clarithromycin levels in all tissues, except the central nervous system, were several times higher than the circulating drug levels. The highest concentrations were usually found in the liver and lung where the tissue to plasma (T/P) ratios reached 10 to 20.
Normal Subjects: In fed patients given 500 mg clarithromycin (Klaricid OD) once-daily, the peak steady state plasma concentration of clarithromycin and 14-OH-clarithromycin were 1.3 and 0.48 μg/ml, respectively. Elimination half-lives of the parent drug and metabolite were approximately 5.3 hours and 7.7 hours, respectively. When clarithromycin (Klaricid OD) 1000 mg once-daily (2 x 500 mg) was administered, the steady state Cmax for clarithromycin and its hydroxylated metabolite averaged 2.4 μg/ml and 0.67 μg/ml, respectively. The half-life of the parent drug at the 1000 mg dose level was approximately 5.8 hours, while that of the 14-OH-clarithromycin was approximately 8.9 hours. The Tmax for both the 500 mg and 1000 mg doses was approximately six hours. At steady state the 14-OH-clarithromycin levels did not increase proportionately with the clarithromycin dose, and the apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at the higher doses. This non-linear pharmacokinetic behavior of clarithromycin, coupled with the overall decrease in the formation of 14-hydroxylation and N-demethylation products at the higher doses, indicates the non-linear metabolism of clarithromycin becomes more pronounced at high doses.
Urinary excretion accounts for approximately 40% of the clarithromycin dose. Fecal elimination accounts for approximately 30%.
Patients: Clarithromycin and its 14-OH metabolite distribute readily into body tissues and fluids. Limited data from a small number of patients suggests clarithromycin does not achieve significant levels in cerebrospinal fluid after oral doses (i.e., only 1 to 2% of serum levels in CSF in patients with normal blood-CSF barriers). Concentrations in tissues are usually several fold higher than serum concentrations.
Hepatic Impairment: In a study comparing one group of healthy human subjects with a group of subjects with liver impairment who were given 250 mg of clarithromycin immediate release b.i.d. for two days and a single 250 mg dose the third day, steady state plasma levels and systemic clearing of clarithromycin were not significantly different between the two groups. In contrast, steady state concentrations of the 14-OH metabolite were markedly lower in the group of hepatic-impaired subjects. This decreased metabolic clearance of the parent compound by 14-hydroxylation was partially offset by an increase in the renal clearance of parent drug, resulting in comparable steady state levels of parent drug in the hepatic impaired and healthy subjects. These results indicate no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function.
Renal Impairment: A study was conducted to evaluate and compare the pharmacokinetic profile of multiple 500 mg oral doses of clarithromycin immediate release in subjects with normal and decreased renal function. The plasma levels, half-life, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and AUC was larger in subjects with renal impairment. Kelim and urinary excretion were lower. 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 (see Dosage & Administration and Contraindications).
Elderly Subjects: A study was also conducted to evaluate and compare the safety and pharmacokinetic profiles of multiple 500 mg oral doses of clarithromycin immediate release in healthy elderly male and female subjects to those in healthy young adult male subjects. In the elderly group, circulating plasma levels were higher and elimination slower than in the younger group for both parent drug and 14-OH metabolite. However, there was no difference between the two groups when renal clearance was correlated with creatinine clearance. It is concluded from those results that any effect on the handling of clarithromycin is related to renal function and not to age per se.
Klaricid Pediatric: Absorption: Initial pharmacokinetic data were obtained with clarithromycin tablet formulations. These data indicated the drug is rapidly absorbed from the gastrointestinal tract and the absolute bioavailability of a clarithromycin 250 mg tablet was approximately 50%. Both the onset of absorption and the formation of the antimicrobially-active metabolite, 14-OH-clarithromycin, were slightly delayed by food, but the extent of bioavailability was not affected by administration of drug in the nonfasting state.
Distribution, Biotransformation and Elimination: In vitro: In vitro studies showed that protein binding of clarithromycin in human plasma averaged about 70% at clinically-relevant concentrations of 0.45 to 4.5 μg/ml.
Normal Subjects: The bioavailability and pharmacokinetics of Clarithromycin Pediatric Suspension were investigated in adult subjects and in pediatric patients. A single-dose study in adult subjects found the overall bioavailability of the pediatric formulation to be equivalent to or slightly greater than that of the tablet (dosage with each was 250 mg). As with the tablet, administration of the pediatric formulation with food leads to a slight delay in the onset of absorption, but does not affect the overall bioavailability of clarithromycin. The comparative clarithromycin Cmax, AUC, and T½ for the pediatric formulation (non fasted state) were 0.95 μg/ml, 6.5 μg hr/ml, and 3.7 hours, respectively, and for the 250 mg tablet (fasted state) were 1.10 μg/ml, 6.3 μg hr/ml, and 3.3 hours, respectively.
In a multiple dose study in which adult subjects were administered 250 mg of the Clarithromycin Pediatric Suspension every 12 hours, steady state blood levels were nearly reached by time of the fifth dose. Pharmacokinetic parameters after the fifth dose for Clarithromycin Pediatric Suspension were: Cmax 1.98 μg/ml, AUC 11.5 μg hr/ml, Tmax 2.8 hours and T½ 3.2 hours for clarithromycin, and 0.67, 5.33, 2.9 and 4.9, respectively, for 14-OH-clarithromycin.
In fasting healthy human subjects, peak serum concentrations were attained within two hours after oral dosing. With b.i.d. dosing using a 250 mg tablet every 12 hours, steady-state peak serum concentrations of clarithromycin were attained in two to three days and were approximately 1 μg/ml. Corresponding peak serum concentrations were 2 to 3 μg/ml with a 500 mg dose administered every 12 hours.
The elimination half-life of clarithromycin was about three to four hours with a 250 mg tablet administered every 12 hours but increased to five to seven hours with 500 mg administered every 12 hours. 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 five to six hours after a dose of 250 mg every 12 hours. With a dose of 500 mg every 12 hours, the peak steady-state concentrations of 14-OH-clarithromycin are slightly higher (up to 1 μg/ml), and its elimination half-life is about seven hours. With either dose, the steady-state concentration of this metabolite is generally attained within two to three days.
Approximately 20% of a 250 mg oral dose given every 12 hours is excreted in the urine as unchanged clarithromycin. After a dose of 500 mg every 12 hours, urinary excretion of unchanged parent drug is approximately 30%. 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 either a 250 mg or 500 mg dose administered every 12 hours.
Patients: Clarithromycin and its 14-OH metabolite distribute readily into body tissues and fluids. Concentrations in tissues are usually several fold higher than serum concentrations. Examples from tissue and serum concentrations are presented in Table 2: See Table 2.

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In pediatric patients requiring oral antibiotic treatment, clarithromycin demonstrated good bioavailability with a pharmacokinetic profile consistent with previous results from adult subjects using the same suspension formulation. The results indicated rapid and extensive drug absorption in children and, except for a slight delay in onset of absorption, food seemed to have no significant effect on drug bioavailability or pharmacokinetic profiles. Steady-state pharmacokinetic parameters obtained after the ninth dose on treatment day five were as follows for the parent drug: Cmax 4.60 μg/ml, AUC 15.7 μg/hr/ml and Tmax 2.8 hr; the corresponding values for the 14-OH metabolite were: 1.64 μg/ml, 6.69 μg/hr/ml, and 2.7 hr, respectively. Elimination half-life was estimated to be approximately 2.2 hr and 4.3 hr for the parent compound and metabolite, respectively.
In another study, information was obtained regarding the penetration of clarithromycin in middle ear fluid in patients with otitis media. Approximately 2.5 hours after receiving the fifth dose (dosage was 7.5 mg/kg b.i.d.), the mean concentration of clarithromycin was 2.53 μg/g fluid in the middle ear and for the 14-OH metabolite was 1.27 μg/g. The concentrations of parent drug and 14-OH metabolite were generally twice as high as the corresponding concentrations in serum.
Hepatic Impairment The steady-state concentrations of clarithromycin in subjects 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 were also altered in subjects with impaired renal function who received multiple 500 mg oral doses. The plasma levels, half-life, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and the AUC was larger in subjects with renal impairment than in 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 (see Dosage & Administration).
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 two 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 to subject 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 (tablets for adults; granular suspension for children) 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 15 to 30 mg/kg/day of clarithromycin in two divided doses, steady-state Cmax values generally ranged from 8 to 20 μg/ml. However, Cmax values as high as 23 μg/ml have been observed in HIV-infected pediatric patients taking 30 mg/kg/day in two 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.
Toxicology: Preclinical safety data: Klaricid/Klaricid OD: Acute, Subchronic, and Chronic Toxicity: Studies were conducted in mice, rats, dogs and/or monkeys with clarithromycin administered orally. The duration of administration ranged from a single oral dose to repeated daily oral administration for six consecutive months.
In acute mouse and rat studies, one rat, but no mice, died following a single gavage of 5 g/kg body weight. The median lethal dose, therefore, was greater than 5 g/kg, the highest feasible dose for administration.
No adverse effects were attributed to clarithromycin in primates exposed to 100 mg/kg/day for 14 consecutive days or to 35 mg/kg/day for one month. Similarly, no adverse effects were seen in rats exposed to 75 mg/kg/day for one month, to 35 mg/kg/day for three months, or to 8 mg/kg/day for six months. Dogs were more sensitive to clarithromycin, tolerating 50 mg/kg/day for 14 days, 10 mg/kg/day for one and three months, and 4 mg/kg/day for six months without adverse effects.
The major clinical signs at toxic doses in these studies described above included emesis, weakness, reduced food consumption and reduced weight gain, salivation, dehydration, and hyperactivity. Two of ten monkeys receiving 400 mg/kg/day died on treatment day eight; yellow discolored feces were passed on a few isolated occasions by some surviving monkeys given a dose of 400 mg/kg/day for 28 days.
The primary target organ at toxic dosages in all species was the liver. The development of hepatotoxicity in all species was detectable by early elevation of serum concentrations of alkaline phosphatase, alanine and aspartate aminotransferase, gamma-glutamyl transferase, and/or lactic dehydrogenase. Discontinuation of the drug generally resulted in a return to or toward normal concentrations of these specific parameters.
Additional tissues less commonly affected in the various studies included the stomach, thymus and other lymphoid tissues, and the kidneys. Conjunctival injection and lacrimation, following near therapeutic dosages, occurred in dogs only. At a massive dosage of 400 mg/kg/day, some dogs and monkeys developed corneal opacities and/or edema.
Fertility, Reproduction, and Teratogenicity: Fertility and reproduction studies have shown daily dosages of 150 to 160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, and number and viability of offspring. Two teratogenicity studies in both Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.) rats, one study in New Zealand White rabbits and one study in cynomolgus monkeys failed to demonstrate any teratogenicity from clarithromycin. Only in one additional study in Sprague-Dawley rats at similar doses and essentially similar conditions did a very low, statistically insignificant incidence (approximately 6%) of cardiovascular anomalies occur. These anomalies appeared to be due to spontaneous expression of genetic changes within the colony. Two studies in mice also revealed a variable incidence of cleft palate (3 to 30%) following doses of 70 times the upper range of the usual daily human clinical dose (500 mg b.i.d.), but not at 35 times the maximal daily human clinical dose, suggesting maternal and fetal toxicity but not teratogenicity.
Clarithromycin has been shown to produce embryonic loss in monkeys when administered at approximately ten times the upper range of the usual daily human dose (500 mg b.i.d.), starting at gestation day 20. This effect has been attributed to maternal toxicity of the drug at very high doses. An additional study in pregnant monkeys at dosages of approximately 2.5 to 5 times the maximal intended daily dosage produced no unique hazard to the conceptus.
A dominant lethal test in mice given 1000 mg/kg/day (approximately 70 times the maximal human daily clinical dose) was clearly negative for any mutagenic activity, and, in a Segment I study of rats treated with up to 500 mg/kg/day (approximately 35 times the maximal daily human clinical dose) for 80 days, no evidence of functional impairment of male fertility due to this long-term exposure to these very high doses of clarithromycin was exhibited.
Mutagenicity: Studies to evaluate the mutagenic potential of clarithromycin were performed using both nonactivated and rat-liver-microsome-activated test systems (Ames Test). Results of these studies provided no evidence of mutagenic potential at drug concentrations of 25 μg/Petri plate or less. At a concentration of 50 μg the drug was toxic for all strains tested.
Klaricid Pediatric: Acute and Subchronic Oral Toxicity Studies: The acute oral LD50 values for a clarithromycin suspension administered to three-day old mice were 1290 mg/kg for males and 1230 mg/kg for females. The LD50 values in three-day old rats were 1330 mg/kg for males and 1270 mg/kg for females. For comparison, the LD50 for orally-administered clarithromycin is about 2700 mg/kg for adult mice and about 3000 mg/kg for adult rats. These results are consistent with other antibiotics of the penicillin group, cephalosporin group and macrolide group in that the LD50 is generally lower in juvenile animals than in adults.
In both mice and rats, body weight was reduced or its increase suppressed and suckling behavior and spontaneous movements were depressed for the first few days following drug administration. Necropsy of animals that died disclosed dark-reddish lungs in mice and about 25% of the rats; rats treated with 2197 mg/kg or more of a clarithromycin suspension were also noted to have a reddish-black substance in the intestines, probably because of bleeding. Deaths of these animals were considered due to debilitation resulting from the depressed suckling behavior or bleeding from the intestines.
Pre-weaning rats (five days old) were administered a clarithromycin suspension formulation for two weeks at doses of 0, 15, 55, and 200 mg/kg/day. Animals from the 200 mg/kg/day group had decreased body-weight gains, decreased mean hemoglobin and hematocrit values, and increased mean relative kidney weights compared to animals from the control group. Treatment-related minimal to mild multifocal vacuolar degeneration of the intrahepatic bile duct epithelium and an increased incidence of nephritic lesions were also observed in animals from this treatment group. The "no-toxic effect" dosage for this study was 55 mg/kg/day.
An oral toxicity study was conducted in which immature rats were administered a clarithromycin suspension for six weeks at daily dosages of 0, 15, 50, and 150 mg base/kg/day. No deaths occurred and the only clinical sign observed was excessive salivation for some of the animals at the highest dosage from one to two hours after administration during the last three weeks of treatment. Rats from the 150 mg/kg dose group had lower mean body weights during the first three weeks, and were observed to have decreased mean serum albumin values and increased mean relative liver weight compared to the controls.
No treatment-related gross or microscopic histopathological changes were found. A dosage of 150 mg/kg/day produced slight toxicity in the treated rats and the "no effect dosage" was considered to be 50 mg/kg/day.
Juvenile beagle dogs, three weeks of age, were treated orally daily for four weeks with 0, 30, 100, or 300 mg/kg of clarithromycin, followed by a four-week recovery period. No deaths occurred and no changes in the general condition of the animals were observed. Necropsy revealed no abnormalities. Upon histological examination, fatty deposition of centrilobular hepatocytes and cell infiltration of portal areas were observed by light microscopy, and an increase in hepatocellular fat droplets was noted by electron microscopy in the 300 mg/kg dose group. The toxic dose in juvenile beagle dogs was considered to be greater than 300 mg/kg and the "no effect dose" 100 mg/kg.
Fertility, Reproduction, and Teratogenicity: Fertility and reproduction studies have shown daily dosages of 150 to 160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, and number and viability of offspring. Two teratogenicity studies in both Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.) rats, one study in New Zealand white rabbits and one study in cynomolgus monkeys failed to demonstrate any teratogenicity from clarithromycin. Only in one additional study in Sprague-Dawley rats at similar doses and essentially similar conditions did a very low, statistically insignificant incidence (approximately 6%) of cardiovascular anomalies occur. These anomalies appeared to be due to spontaneous expression of genetic changes within the colony. Two studies in mice also revealed a variable incidence of cleft palate (3 to 30%) following doses of 70 times the upper range of the usual daily human clinical dose (500 mg, b.i.d.), but not at 35 times the maximal daily human clinical dose, suggesting maternal and fetal toxicity but not teratogenicity.
Clarithromycin has been shown to produce embryonic loss in monkeys when administered at approximately ten times the upper range of the usual daily human dose (500 mg b.i.d.), starting at gestation day 20. This effect has been attributed to maternal toxicity of the drug at very high doses. An additional study in pregnant monkeys at dosages of approximately 2.5 to 5 times the maximal intended daily dosage of 500 mg b.i.d. produced no unique hazard to the conceptus.
A dominant lethal test in mice given 1000 mg/kg/day (approximately 70 times the maximal human daily clinical dose of 500 mg b.i.d.) was clearly negative for any mutagenic activity, and, in a Segment I study of rats treated with up to 500 mg/kg/day (approximately 35 times the maximal daily human clinical dose of 500 mg b.i.d.) for 80 days, no evidence of functional impairment of male fertility due to this long-term exposure to these very high doses of clarithromycin was exhibited.
Mutagenicity: Studies to evaluate the mutagenic potential of clarithromycin were performed using both nonactivated and rat-liver-microsome-activated test systems (Ames Test). Results of these studies provided no evidence of mutagenic potential at drug concentrations of 25 μg/Petri plate or less. At a concentration of 50 μg the drug was toxic for all strains tested.
Microbiology: Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunits of susceptible bacteria and suppressing 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 (MIC's) of clarithromycin are generally one log2 dilution more potent than the MIC's of erythromycin.
In vitro data also indicate 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 this antibiotic has activity against clinically significant mycobacterial species. The in vitro data indicate Enterobacteriaceae, pseudomonas species and other non-lactose fermenting Gram-negative bacilli are not susceptible to clarithromycin.
Clarithromycin has been shown to be active against most strains of the following micro-organisms both in vitro and in clinical infections as described in Indications: 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 pneumophila.
Other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium, Mycobacterium intracellulare.
Beta-lactamase production should have no effect on clarithromycin activity.
NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.
Helicobacter: Helicobacter pylori: In cultures performed prior to therapy, H. pylori was isolated and clarithromycin MIC’s were determined pre-treatment in 104 patients. Of these, four patients had resistant strains, two patients had strains with intermediate susceptibility, and 98 patients had susceptible strains.
The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci (Group C,F,G), Viridans group streptococci.
Aerobic Gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida.
Anaerobic Gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic Gram-negative microorganisms: Bacteroides melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
The principal metabolite of clarithromycin in man and other primates is a microbiologically- active metabolite, 14-OH-clarithromycin. This metabolite is as active or 1- to 2-fold less active than the parent compound for most organisms, except for H. influenzae against which it is twice as active. The parent compound and the 14-OH metabolite exert either an additive or synergistic effect on H. influenzae in vitro and in vivo, depending on bacterial strains.
Clarithromycin was found to be two to ten times more active than erythromycin in several experimental animal infection models. It was shown, for example, to be more effective than erythromycin in mouse systemic infection, mouse subcutaneous abscess, and mouse respiratory tract infections caused by S. pneumoniae, S. aureus, S. pyogenes, and H. influenzae. In guinea pigs with Legionella infection this effect was more pronounced; an intraperitoneal dose of 1.6 mg/kg/day of clarithromycin was more effective than 50 mg/kg/day of erythromycin.
Susceptibility Tests: Quantitative methods that require measurement of zone diameters give the most precise estimates of susceptibility of bacteria to antimicrobial agents. One recommended procedure uses discs impregnated with 15 μg of clarithromycin for testing susceptibility (Kirby-Bauer diffusion test); interpretations correlate inhibition zone diameters of this disc test with MIC values for clarithromycin. The MICs are determined by the broth or agar dilution method.
With these procedures, a report from the laboratory of "susceptible" indicates the infecting organism is likely to respond to therapy. A report of "resistant" indicates the infective organism is not likely to respond to therapy. A report of "Intermediate Susceptibility" suggests the therapeutic effect of the drug may be equivocal or the organism would be susceptible if higher doses were used. (Intermediate susceptibility is also referred to as moderately susceptible.)
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