Klacid/Klacid MR

Clarithromycin.

Klacid FC tab: One tablet contains 500 mg Clarithromycin.
Tablet sodium content: 6.1mg per tablet.
Klacid granules for oral susp 125 mg/5 mL: Each 5ml of the granules contains 125mg of clarithromycin.
Excipients: Sucrose 550mg/ml.
Klacid granules for oral susp 250 mg/5 mL: Clarithromycin Pediatric Suspension consists of a granulation of clarithromycin and Carbopol which is coated with HP-55 polymer (hydroxypropyl methylcellulose phthalate). The coated granules are mixed with a blend of inactive ingredients, such as sucrose, xanthan gum, silicon dioxide, potassium sorbate, citric acid, maltodextrin, titanium dioxide, flavoring, etc. Water is added to reconstitute the suspension prior to use. After mixing, each 5 mL of the granules for suspension contains 250mg of clarithromycin.
Klacid MR tab: One tablet contains 500 mg Clarithromycin.
Excipient: Lactose 115mg per tablet.
Tablet sodium content: 15.3mg per tablet
Excipients/Inactive Ingredients: Klacid FC tab: Tablet Core: Sodium croscarmellose, Microcrystalline cellulose, Silicon dioxide, Povidone, Stearic acid, Magnesium stearate, Talc.
Coating Solution: Hypromellose, Sorbitan monooleate, Propylene glycol, Titanium dioxide, Vanillin, Quinoline Yellow (E104 aluminium lake), Sorbic acid.
Klacid MR tab: Tablet Core: Citric acid, Sodium alginate, Sodium calcium alginate, Lactose, Povidone, Talc, Stearic acid, Magnesium stearate.
Coating Solution: Hypromellose, Polyethylene glycol, Titanium dioxide, Quinoline Yellow (E104 aluminium lake), Sorbic acid.

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.
Klacid granules for oral susp 250 mg/5 mL: Clarithromycin Pediatric Suspension is an oral dosage form of clarithromycin for use primarily in children.
Clinical Studies: Clarithromycin Granules for Oral Suspension: 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: Absorption: Klacid FC tab: 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.
Klacid granules for oral susp: 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, 14OH-clarithromycin, were slightly delayed by food, but the extent of bioavailability was not affected by administration of drug in the nonfasting state.
Klacid MR tab: The kinetics of orally administered clarithromycin MR 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, with the MR tablets taken with food. 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 followingin vitro and in vivo data is applicable to the modified release formulation. Concomitant food intake increases the exposure to clarithromycin. Therefore, clarithromycin MR tablets should be taken with 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 mcg/mL.
Klacid tablet: A decrease in binding to 41% at 45.0 mcg/mL suggested the binding sites might become saturated, but this only occurred at concentrations far in excess of the therapeutic drug levels.
In vivo: Klacid tablet: 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: Klacid FC tab: 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 mcg/mL for clarithromycin and 0.6 mcg/mL for 14-hydroxyclarithromycin, 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 mcg/mL; its hydroxylated metabolite averaged 0.88 and 0.83 mcg/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-hydroxyclarithromycin was 6.9 to 8.7 hours. At steady state the 14-hydroxyclarithromycin 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 14hydroxylation 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.
Klacid granules for oral susp: 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 T ½ 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 T ½ 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.
Klacid MR tab: In fed patients given 500 mg clarithromycin MR 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 5.3hours and 7.7hours, respectively. When clarithromycin MR 1000 mg once-daily (2 x 500 mg) was administered, the steady state Cmax for clarithromycin and its hydroxylated metabolite averaged 2.4μg/ml and 0.67μg/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 T_max 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.Concentrations in tissues are usually several fold higher than serum concentrations.
Klacid tablet: 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).
Klacid FC tab, Klacid granules for oral susp: Examples from tissue and serum concentrations are presented as follows. (See Table 1.)

Click on icon to see table/diagram/image

Klacid granules for oral susp: 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 affect 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 mcg/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 mcg/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: Klacid tablet: 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.
Klacid granules for oral susp: 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: Klacid tablet: 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 CONTRAINDICATIONS and DOSAGE & ADMINISTRATION).
Klacid granules for oral susp: 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-H 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: Klacid tablet: 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.
Klacid granules for oral susp: 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.
Mycobacterium Avium Infections: Klacid FC tab: 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 mcg/mL and 5 to 10 mcg/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.
Klacid granules for oral susp: 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 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 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.
Concomitant Omeprazole Administration: Klacid FC tab: 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 mcg/mL and the mean Cmin value was approximately 1.8 mcg/mL. The mean AUC0-8 for clarithromycin was 22.9 mcg/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 T1/2 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.
Toxicology: Pre-Clinical Safety Data: Acute, Subchronic, and Chronic Toxicity: Klacid tablet: 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 previously described 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.
Klacid granules for oral susp: 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 in female rats have shown that daily dosages of 150 mg/kg/day (highest dose tested) caused no adverse effects on the estrous cycle, fertility, parturition, and number and viability of offspring. In male rats there was no evidence of adverse toxicity on fertility up to 250mg/kg. 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 non-activated and rat-liver-microsome-activated test systems (Ames Test). Results of these studies provided no evidence of mutagenic potential at drug concentrations of 25 mcg/Petri plate or less. At a concentration of 50 mcg 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 sensitive to clarithromycin.
Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described under 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 mcg of clarithromycin for testing susceptibility (Kirby-Bauer diffusion test); interpretations correlate inhibition zone diameters of this disc test with MIC values for clarithromycin. The MIC's 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.)

Klacid FC tab: Clarithromycin is indicated for treatment of infections due to susceptible organisms in adults and children 12 years and older. Such infections include: Treatment of infections caused by pathogens sensitive to Clarithromycin.
Infection of nose-pharynx tract (tonsillitis, pharyngitis) and of paranasal sinuses.
Infections of lower respiratory tract: bronchitis, bacterial pneumonia and atypical pneumonia.
Skin infections: impetigo, erysipelas, folliculitis, furunculosis and septic wounds.
Eradication of H.pylori in patients with duodenal ulcers in the presence of acid suppression effected by omeprazole.
Klacid granules for oral susp: Clarithromycin is indicated for treatment of infections due to susceptible organisms in children 6 months to 12 years. Such infections include: 1. Upper respiratory infections (e.g., streptococcal pharyngitis).
2. Lower respiratory infections (e.g., bronchitis, pneumonia).
3. Acute otitis media.
4. Skin and skin structure infections (e.g., impetigo, folliculitis, cellulitis, abscesses).
5. Disseminated or localized mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare. Localized infections due to Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.
Klacid MR tab: Clarithromycin is indicated for treatment of infections due to susceptible organisms. Such infections include: 1. Lower respiratory tract infections (e.g., bronchitis, pneumonia).
2. Upper respiratory tract infections (e.g., pharyngitis, sinusitis).
3. Skin and soft tissue infections (e.g., folliculitis, cellulitis, erysipelas).

Klacid FC Tablet: For oral use.
Adults: The usual recommended dosage of clarithromycin in adults and children 12 years of age or older, is one 250mg tablet twice daily. In more severe infections, the dosage can be increased to 500mg twice daily. The usual duration of therapy is 5 to 14 days, excluding treatment of community acquired pneumonia and sinusitis which require 6 to 14 days of therapy.
Eradication of H.pylori in patients with duodenal ulcers: Adults: The usual dose of Clarithromycin is 500 mg three times daily for 14 days.
Dual therapy: Klacid should be administered with oral omeprazole 40 mg once daily. The pivotal study was conducted with omeprazole 40 mg once daily for 28 days. Supportive studies have been conducted with omeprazole 40 mg once daily for 14 days.
Triple Therapy: Klacid 500 mg twice daily should be given with amoxycillin 1000mg twice daily and omeprazole 20 mg daily for 10 days.
Elderly: As for adults.
Renal impairment: In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage of clarithromycin should be reduced by one-half, i.e., 250 mg once daily, or 250 mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.
Pediatric Population: The use of clarithromycin IR has not been studied in children less than 12 years of age.
Klacid granules for oral susp: Pediatric patients under 12 years of age: Clinical trials have been conducted using clarithromycin pediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin pediatric suspension (granules for oral suspension).
The recommended daily dosage of Clarithromycin Pediatric Suspension (125 mg/5 mL or 250 mg/5 mL) in children is 7.5 mg/kg b.i.d. up to a maximum dose of 500 mg b.i.d. for non-mycobacterial infections. The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. The prepared suspension can be taken with or without meals, and can be taken with milk.
The following table is a suggested guide for determining dosage based on the weight of the child and the concentration of the suspension: (See Tables 2 and 3.)

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Dosage in Patients with Mycobacterial Infections: Klacid granules for oral susp 125 mg/5 mL: In children with disseminated or localized mycobacterial infections (M. avium, M. intracellulare, M. chelonae, M. fortuitum, M. kansasii), the recommended dose is 7.5 to 15mg/g clarithromycin b.i.d, not exceeding a maximum dose of 500mg b.i.d.
Treatment with clarithromycin should continue as long as clinical benefit is demonstrated. The addition of other antimycobacterial agents may be of benefit. (See Table 4.)

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Klacid granules for oral susp 250 mg/5 mL: In children with disseminated or localized mycobacterial infections (M. avium, M. intracellulare, M. chelonae, M. fortuitum, M. kansasii), the recommended dose is 15 to 30 mg/kg clarithromycin per day in two divided doses.
Treatment with clarithromycin should continue as long as clinical benefit is demonstrated. The addition of other antimycobacterial agents may be of benefit. (See Table 5.)

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Renal Impairment: In children with creatinine clearance less than 30 ml/min, the dosage of clarithromycin 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.
Preparation for Use: An appropriate amount of water, consult your approved International Manufacturing Formula, should be added to the granules in the bottle and shaken until all of the particles are suspended. Avoid vigorous and/or lengthy shaking. Shake prior to each subsequent use to ensure resuspension. The concentration of clarithromycin in the reconstituted suspension is 125 mg /5 mL or 250mg per 5 ml.
Administration: Several devices can be used to dose and administer Clarithromycin Pediatric Suspension.
Conservation: After reconstitution, store at room temperature (15°C to 30°C) and use within 14 days. Do not refrigerate.
Swirl well before each use.
Klacid MR Tablet: For oral use.
Adults: The usual recommended dosage of clarithromycin MR tablets in adults and children 12 years of age or older is 500 mg once-daily with food. In more severe infections, the dosage may be increased to 1000 mg once- daily (2 x 500 mg). The usual duration of therapy is 5 to 14 days, excluding treatment of community acquired pneumonia and sinusitis which require 6 to 14 days therapy.
Do not crush or chew clarithromycin modified release tablets.
Renal Impairment: In patients with severe renal impairment (creatinine clearance less than 30 mL/min), the usual recommended dose is 250 mg once daily. Because the modified-release tablet cannot be split, instead immediate-release tablets should be used. In more severe infections, the recommended dose is one 500mg modified-release tablet once daily. No dose adjustment is required for patients with moderate renal impairment (creatinine clearance 30 to 60 ml/min).
Pediatric Population: The use of clarithromycin MR has not been studied in children less than 12 years of age.

Symptoms: Reports indicate the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of clarithromycin and showed altered mental status, paranoid behavior, hypokalemia, and hypoxemia.
Treatment: Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

Hypersensitivity to macrolide antibiotic drugs or any of the excipients (see DESCRIPTION).
Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, domperidone, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see INTERACTIONS).
Concomitant administration of clarithromycin and ergot alkaloids (e.g., ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see INTERACTIONS).
Concomitant administration of clarithromycin and oral midazolam is contraindicated (see INTERACTIONS).
Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointes (see PRECAUTIONS and INTERACTIONS).
Clarithromycin should not be given to patients with electrolyte disturbances (hypokalemia or hypomagnesaemia, due to the risk of prolongation of the QT interval.
Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins), that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see PRECAUTIONS).
Clarithromycin (and other strong CYP3A4 inhibitors) should not be used concomitantly with colchicine (see PRECAUTIONS and INTERACTIONS).
Concomitant administration with ticagrelor or ranolazine is contraindicated.
Concomitant administration of clarithromycin and lomitapide is contraindicated (see INTERACTIONS).

Use of any antimicrobial therapy, such as clarithromycin, to treat H.pylori infection may select for drug-resistant organisms.
The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy.
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.
Clarithromycin is principally metabolized by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.
Caution is advised in patients with severe renal insufficiency.
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. 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, which may lead to overgrowth of C. difficile. 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.
Colchicine: 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 INTERACTIONS). Concomitant administration of clarithromycin and colchicine is contraindicated (see CONTRAINDICATIONS).
Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see INTERACTIONS).
Cardiovascular Events: Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including clarithromycin (see ADVERSE REACTIONS). Therefore, as the following situations may lead to an increased risk for ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in the following patients: Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia; Clarithromycin must not be given to patients with hypokalaemia or hypomagnesaemia (see CONTRAINDICATIONS); Patients concomitantly taking other medicinal products associated with QT prolongation (see INTERACTIONS); Concomitant administration of clarithromycin with astemizole, cisapride, domperidone, pimozide and terfenadine is contraindicated (see CONTRAINDICATIONS); Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see CONTRAINDICATIONS).
Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short-term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing clarithromycin.
Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.
Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis, DRESS, and Henoch-Schonlein purpura clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see INTERACTIONS).
Attention should also be paid to the possibility of cross-resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS).
Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see INTERACTIONS).
Oral Hypoglycemic Agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycemia. Careful monitoring of glucose is recommended.
Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
Caution should be exercised when clarithromycin is co-administered with direct acting oral anticoagulants such as dabigatran, rivaroxaban and apixaban, particularly to patients at high risk of bleeding (see INTERACTIONS).
Excipients: Klacid granules for oral susp: Clarithromycin Granules for Oral Suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
When prescribing to diabetic patients, the sucrose content should be taken into account.
Klacid MR Tablet: Clarithromycin Modified Release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take these medicines.
Clarithromycin Modified Release tablets contain 15.3 mg sodium per tablet. If patients receive two Modified Release tablets once daily, the resulting sodium amount (in total 30.6 mg per dose) should be taken into consideration for patients on a controlled sodium diet.
Effects on ability to drive and use machines: There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

Pregnancy: The safety of clarithromycin for use in pregnancy has not been established. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimester have reported an increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major congenital malformations will use of macrolides including clarithromycin during pregnancy provide conflicting results. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risks.
Breastfeeding: Clarithromycin is excreted into human breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive about 1.7% of maternal weight-adjusted dose of clarithromycin.
The safety of clarithromycin use during breast-feeding of infants has not been established.
Fertility: In the rat, fertility studies have not shown any evidence of harmful effects (see PHARMACOLOGY: TOXICOLOGY: PRE-CLINICAL SAFETY DATA UNDER ACTIONS).

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics.
There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.
The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin IR, granules for oral suspension, IV, MR and ER.
The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed. (See Table 6.)

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There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Immunocompromised Patients: In AIDS 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.
In adult patients, the most frequently reported adverse events by patients treated with total daily doses of 1000 mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing disturbance, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) elevations. Additional low-frequency events included dyspnea, insomnia, and dry mouth.
In these immunocompromised patients evaluations of laboratory values were made by analyzing those values outside the seriously abnormal level (i.e., the extreme high or low limit) for the specified test. On the basis of this criteria, about 2 to 3% of these patients who received 1000 mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients also had elevated BUN levels.

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Cisapride, domperidone, pimozide, astemizole and terfenadine: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see CONTRAINDICATIONS).
Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see CONTRAINDICATIONS). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval, which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergot alkaloids: Postmarketing reports indicate that co-administration 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 and ergot alkaloids is contraindicated (see CONTRAINDICATIONS).
Oral Midazolam: When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 7-fold after oral administration of midazolam. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see CONTRAINDICATIONS).
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS) as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g.fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.
Lomitapide: Concomitant administration of clarithromycin with lomitapide is contraindicated due to the potential for markedly increased transaminases (see CONTRAINDICATIONS).
Effects of Other Medicinal Products on Clarithromycin: Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.
The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.
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(R)-hydroxy-clarithromycin (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.
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole: 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 minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir: A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. 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%, resulting in a maximum dose of one clarithromycin modified release tablet per day. For patients with CL_CR <30 mL/min) the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 gm/day should not be co-administered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see Bi-directional Drug Interactions as follows).
Effect of Clarithromycin on Other Medicinal Products: Antiarrhythmics: There have been postmarketed 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 levels of these medications should be monitored during clarithromycin therapy.
There have been post marketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Oral hypoglycemic agents/Insulin: With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended.
CYP3A-based Interactions: 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 drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, domperidone, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.
Direct acting oral anticoagulants (DOACs): The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolized via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents particularly to patients at high risk of bleeding (see PRECAUTIONS).
Omeprazole: Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC_0-24, and t_1/2 increased by 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 omeprazole was co-administered with clarithromycin.
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. Co-administration 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.
Theophylline, carbamazepine: Results of clinical studies indicate there was a modest but statistically significant (p ≤ 0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly 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. Drug delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the drug, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration. 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.
Other Drug Interactions: Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and PRECAUTIONS).
Digoxin: 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 post marketing 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.
Zidovudine: Simultaneous oral administration of clarithromycin immediate release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.
Phenytoin and Valproate: There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs not thought to be metabolized by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Bi-directional Drug Interactions: 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 <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 co-administered with protease inhibitors.
Calcium Channel Blockers: Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
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 effect.
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 Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone.
Clarithromycin AUC and Cmax 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 interaction 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 INTERACTIONS).

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Klacid Tablet: Store below 30°C. Store in dry place and protect from light.
Shelf life: 36 months.
Klacid granules for oral susp 125 mg/5 mL: Clarithromycin Pediatric Suspension granules should be stored at room temperature (store below 30° C) in a well-closed container. Do not refrigerate the reconstituted suspension; store at room temperature.
Shelf life: 24 months.
Klacid granules for oral susp 250 mg/5 mL: Clarithromycin Pediatric Suspension granules should be stored below 30°C in a well-closed container. Do not refrigerate the reconstituted suspension; store below 30°C.
Shelf life: 36 months.

Macrolides

J01FA09 - clarithromycin ; Belongs to the class of macrolides. Used in the systemic treatment of infections.

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