Clarithromycin

The manufacturer of darifenacin states that darifenacin dosage should not exceed 7.5 mg daily in patients receiving the drug concomitantly with potent CYP3A4 inhibitors, including clarithromycin.

Concomitant administration of clarithromycin and cisapride is contraindicated. Coadministration of clarithromycin and/or erythromycin with cisapride has been associated with QT prolongation and serious cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes); fatalities have been reported. In 2 patients with chronic renal failure who were receiving cisapride (10 mg 3-4 times daily), QT prolongation and/or torsades de pointes occurred within several days after initiating therapy with clarithromycin (500 mg twice daily). Elevated serum cisapride concentrations observed in one patient decreased following discontinuance of clarithromycin.

Clarithromycin should be used with caution in patients receiving carbamazepine; if such concomitant therapy is used, a reduction in carbamazepine dosage and/or monitoring of plasma carbamazepine concentrations is advised. Limited data in healthy men indicate that clarithromycin may increase area under the serum concentration-time curve (AUC) for carbamazepine and decrease peak serum concentration and AUC for carbamazepine 10,11-epoxide (CBZ-E).2 51 In addition, increased plasma concentrations of carbamazepine (but not CBZ-E) and, in some patients, manifestations of carbamazepine toxicity (i.e., drowsiness, dizziness, ataxia) occurred within 3-5 days after initiation of clarithromycin therapy (200 mg twice daily) in several patients receiving carbamazepine (600 mg/day) with or without other drugs; plasma carbamazepine concentrations decreased and toxic manifestations subsided within several days following carbamazepine discontinuation.

The manufacturer of eszopiclone states that eszopiclone dosage should be reduced if the drug is used concomitantly with a potent CYP3A4 inhibitor, including clarithromycin. In such situations, the initial eszopiclone dosage should not exceed 1 mg but may be increased to 2 mg if clinically indicated.457

For more Interactions (Complete) data for Clarithromycin (36 total), please visit the HSDB record page.

Clarithromycin, like other macrolide antibiotics, has been linked to a low rate of acute, transient and usually asymptomatic elevations in serum aminotransferase levels which occur in 1% to 2% of patients treated for short periods and a somewhat higher proportion of patients given clarithromycin long term. Asymptomatic elevations in serum enzymes are particularly common among elderly patients given higher doses of clarithromycin.

EC50; Species: Ceriodaphnia dubia (Water Flea) age <24 hr; Conditions: freshwater, static, 25 °C; Concentration: 18660 ug/L for 24 hr (95% confidence interval: 15990-21770 ug/L); Effect: intoxication, immobilization />99% purity formulation/

EC50; Species: Ceriodaphnia dubia (Water Flea) age <24 hr; Conditions: freshwater, renewal, 25 °C, dissolved oxygen >90% saturated; Concentration: 8160 ug/L for 48 hr (95% confidence interval: 2700-18520 ug/L); Effect: decreased population abundance />99% purity formulation/

EC50; Species: Pseudokirchneriella subcapitata (Green Algae) exponential growth phase (Log) 1000 cells/mL; Conditions: freshwater, static, 25 °C, dissolved oxygen >90% saturated; Concentration: 2 ug/L for 3 days (95% confidence interval: 1.9-2.8 ug/L); Effect: decreased population abundance />99% purity formulation/

EC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 20 °C; Concentration: 25720 ug/L for 24 hr (95% confidence interval: 21720-30450 ug/L); Effect: intoxication, immobilization />99% purity formulation/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 150(SRC), determined from a log Kow of 3.16(2) and a regression-derived equation(3), indicates that clarithromycin is expected to have moderate mobility in soil(SRC). The pKa of clarithromycin is 8.99(2), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Clarithromycin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-25 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Utilizing the Closed Bottle test, 0% of the Theoretical BOD was reached in 4 weeks(6) indicating that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 150(SRC), determined from a log Kow of 3.16(2) and a regression-derived equation(3), indicates that clarithromycin is expected to adsorb to suspended solids and sediment(SRC). A pKa of 8.99(2) indicates clarithromycin will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 56(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Utilizing the Closed Bottle test, 0% of the Theoretical BOD was reached in 4 weeks(5) indicating that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), clarithromycin, which has an estimated vapor pressure of 2.3X10-25 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase clarithromycin may be removed from the air by wet or dry deposition(SRC). Clarithromycin has a reported UV max of 288 nm in methanol(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

/AQUATIC SPECIES/ The growth-inhibiting and binary joint effects of 12 antibacterial agents on the freshwater green alga Pseudokirchneriella subcapitata (Korschikov) Hindak were investigated over 72-hr exposures. The toxicity values (the median inhibitory concentration value, in micromoles) in decreasing order of sensitivity were triclosan (0.0018) > triclocarban (0.054) > roxithromycin (0.056) > clarithromycin (0.062) > tylosin (0.20) > tetracycline (2.25) > chlortetracycline (3.49) > norfloxacin (5.64) > sulfamethoxazole (7.50) > ciprofloxacin (20.22) > sulfamethazine (31.26) > trimethoprim (137.78). Several of these antibacterial compounds would be toxic at the micrograms per liter concentrations reported in surface waters and sewage effluents. Simple additive effects were observed in binary mixtures of sulfonamides, and most tylosin, triclosan, or triclocarban combinations. Potentially synergistic effects were observed in binary mixtures of the same class, such as macrolides, tetracyclines, and fluoroquinolones, as well as in some combined drugs, such as trimethoprim and sulfonamides or tylosin and tetracyclines. Potentially antagonistic effects were only observed between tylosin and triclocarban, triclosan and norfloxacin, and triclocarban and norfloxacin. Although present at low concentrations in the aquatic environment, mixtures of these antibacterial agents can potentially affect algal growth in freshwater systems due to their combined action.

/AQUATIC SPECIES/ Recent evidence indicates that a variety of antibiotic residues may affect the integrity of streams located downstream from wastewater treatment plants. Aquatic communities comprising bacterial and fungal decomposers and invertebrate detritivores (shredders) play an important role in the decomposition of allochthonous leaf litter, which acts as a primary energy source for small running waters. The aim of the present study was to assess whether an antibiotic mixture consisting of sulfamethoxazole, trimethoprim, erythromycin-H2O, roxithromycin, and clarithromycin has an effect on such a decomposer-detritivore system. Leaf discs were exposed to these antibiotics (total concentration of 2 or 200 ug/L) for approximately 20 days before offering these discs and corresponding control discs to an amphipod shredder, Gammarus fossarum, in a food choice experiment. Gammarus preferred the leaf discs conditioned in the presence of the antibiotic mixture at 200 ug/L over the control discs (pair-wise t test; p = 0.006). A similar tendency, while not significant, was observed for leaves conditioned with antibiotics at a concentration of 2 ug/L. The number of bacteria associated with leaves did not differ between treatments at either antibiotic concentration (t test; p = 0.57). In contrast, fungal biomass (measured as ergosterol) was significantly higher in the 200 ug/L treatment (t test; p = 0.038), suggesting that the preference of Gammarus may be related to a shift in fungal communities. Overall these results indicate that mixtures of antibiotics may disrupt important ecosystem processes such as organic matter flow in stream ecosystems, although effects are likely to be weak at antibiotic concentrations typical of streams receiving wastewater treatment plant effluents.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of June 21, 2012: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=81103-11-9]

Clarithromycin exhibited a median concentration of 0.87 ug/L (0.536 ug/L maximum) in 8 wastewater treatment plant final effluents sampled in five Canadian cities during 2002; detection limit = 0.001 ug/L(1). Clarithromycin was detected in one of 5 influent samples at a concentration of 112 ng/L (Feb 9, 2007) (limit of detection was 1 ng/L); it was not detected in effluent samples. Sampling took place at a wastewater treatment plant in Kentucky serving a local community of approximately 15,000 with an additional influx of approximately 10,000 students, academic year 2006-2007(2). Median concentrations of clarithromycin were 380 ng/L in raw influents and 240 ng/L in tertiary effluents of conventional wastewater treatment employed in Zurich, Switzerland(3). Clarithromycin concentration ranges in treated effluents of 3 wastewater treatment plants (Zurich-Werdhoelzli, Kloten-Opfikon, and Duebendorf, Switzerland) were 194-328, 97-163, and 57-135 ng/L, respectively; sampling was conducted in July 2000(4). The influent and effluent load ranges of not detected to 46 and not detected to 421 mg/day/100 inhabitants, respectively, was reported in the analysis of 6 sewage treatment plants located in Italy (Cagliari, Naples, Latina, Cuneo, Varese Olona, Varese Lago); median concentrations were 21 and 55 mg/day/100 inhabitants, respectively(5). The compound was reported in effluents from 9 Italian sewage treatment plants at a median concentration of 18.1 ng/L(6). Clarithromycin exhibited percent frequencies of detection of 77, 85, and 83 in waste water influent, effluent, and sewage sludge, respectively, based on analysis of 3 wastewater treatment plants in Catalonia, Spain during 8 sampling campaigns. Limits of detection were 5.0 ng/L, 4.0 ng/L and 7.1 ng/g in influent, effluent and sludge, respectively(7). Clarithromycin concentrations in sewage water effluents of the Netherlands in 2002 ranged from approximately 120 to 550 ng/L(8).

The Koc of clarithromycin is estimated as 150(SRC), using a log Kow of 3.16(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that clarithromycin is expected to have moderate mobility in soil. The pKa of clarithromycin is 8.99(1), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

Using a 2.4 meter soil column, treated effluent was applied to the top of the column over 23 days, simulating a recharge condition similar to those in arid or semiarid climates. The soil used was a Mohall-Laveen sandy loam from an area northwest of Phoenix, AZ with no known history of cultivation or irrigation. Secondarily treated effluent from a 17.5 million gallon/day municipal waste water treatment plant serving 120,000-150,000 residents near Phoenix, AZ was employed. Clarithromycin was not detected in the outflow of the column; reporting limit not determined(1). Clarithromycin was shown to absorb to suspended solids and sludge during waste water treatment plant processes; Kd values in activated sludge were 300 and 400 for October 2003 and February 2004, respectively, at municipal treatment facilities in Switzerland (a KD of 262 was reported for an unspecified field study)(2). Percentage of attenuation in surface water particulates was reported as 41% in a study of the River Olona which receives effluent from the Varese Olona Sewage Treatment Plant, Italy(3).

/CASE REPORTS/ Myelotoxicity, a major toxicity of vinorelbine. may be related to the degree of one's exposure to vinorelbine. In theory, clarithromycin has the potential to alter vinorelbine's pharmacokinetics by inhibiting CYP3A and/or P-glycoprotein; this may result in massive exposure to vinorelbine and severe toxicity. ... A total of 12 (63.2%) and 11 (27.5%) episodes of grade 3/4 neutropenia occurred among the patients who were and were not administered clarithromycin, respectively. The incidence of grade 4 neutropenia was higher in the group administered clarithromycin than in those who did not receive it (31.6% vs 2.5%; p = 0.0033). Vinorelbine dose, concomitant clarithromycin administration, and female sex were significantly correlated with severe neutropenia, with unadjusted odds ratios of 0.07 (95% CI 0.01 to 0.59), 4.52 (95% CI 1.41 to 14.45), and 4.55 (95% CI 1.39 to 14.29), respectively. Compared with patients who are administered vinorelbine alone, patients who are administered clarithromycin during chemotherapy with vinorelbine are at a higher risk for severe neutropenia. Physicians should educate their patients about this interaction. If possible, clarithromycin administration should be avoided in patients who will undergo chemotherapy with vinorelbine in the near future. However, further prospective pharmacokinetic studies are required to confirm this interaction.

/CASE REPORTS/ The case is presented of a 70-yr-old woman who developed prolonged QT syndrome following treatment with 250 mg oral clarithromycin twice daily for 4 days. Concomitant therapy included sotalol, nitroglycerin, prednisone, hydroxychloroquine, and methotrexate. Before beginning clarithromycin, the patient had a QTc of 440/498 msec. After 4 days of clarithromycin therapy, the QT/QTc was 696/641 msec. Clarithromycin and sotalol were discontinued. Over the next 5 days, QT/QTc returned to normal values, resting heart rate increased, and the patient had no syncopal or ischemic pain episodes. She was discharged on her previous medications with the exception of clarithromycin and sotalol. The suggestion that clarithromycin contributed to QT prolongation was supported by a lack of symptoms during 3 months of sotalol therapy before initiation of clarithromycin, rapid prolongation of the QT after clarithromycin initiation, and reversal upon stopping clarithromycin and sotalol

/CASE REPORTS/ A case of an acute toxic cholestatic reaction to clarithromycin, proven by liver biopsy, in a patient with comorbid diseases, prior exposure to erythromycin and ultimate death /is reported/. No autopsy was performed. A 59-year-old woman with diabetes mellitus and chronic renal insufficiency received clarithromycin 500 mg twice daily for 3 days for acute maxillary sinusitis and then developed a rash and jaundice. She was hospitalized 11 days after stopping clarithromycin. Progressive cholestatic jaundice accompanied by oligo-anuric renal failure requiring hemodialysis ensued. Liver biopsy showed pure bilirubinostasis without parenchymal inflammation. On the 22nd hospital day, after clinical deterioration, she died from an apparent cardiopulmonary death. ...

AEROBIC: Clarithromycin, present at 2.43 mg/L, reached -3 and 0% of its theoretical BOD in 14 and 28 days, respectively, using a sewage inoculum at 2 drops/L in the Closed Bottle test(1). Clarithromycin was not removed in sewage treatment plants equipped with pretreatment, primary settling and activated sludge processes(2). In a mass balance assessment study, 1% persisted in sludge, 79% is released in effluents, and 20% is lost to degradation or otherwise unaccounted for during sewage treatment(3). Clarithromycin present at 3000 ng/g biosolid and stored under aerobic conditions exhibited a degradation rate constant of 0.596/day, 50% dissipation time of 1.2 days(4).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clarithromycin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Use (kg) in Switzerland (2009): >1000

Preparation: Y. Watanable, et al., EP 41355; eidem, US 4331803 (1981, 1982 both to Taisho)

Antibiotics are fermentation products and are isolated either as unfinished products or as intermediates, generally solid substances of limited stability. They are purified by methods normally employed in organic chemistry, which include chromatography, crystallization, and precipitation. /Antibiotics/

Table: Clarithromycin Preparations [Table#8043]

Table: Clarithromycin Combinations [Table#8044]

Trade Names: Clarosip /Grunenthal/; Clathromycin /Taisho/; Cyllind /Abbott/; Klacid /Abbott/; Klaricid /Abbott/; Macladin /Guidotti/; Naxy /Sanofi Winthrop/; Veclam /Zambon/; Zeclar /Abbott/.

Pharmaceuticals

Pharmaceuticals -> Antiinfectives for systemic use -> Antibacterials for systemic use -> Macrolides, lincosamines and streptogramins -> Macrolides -> Antibiotics