Klacid

Clarithromycin.

Film-coated tablet: One tablet contains either 250 or 500 mg of clarithromycin.
Modified-release tablet: Yellow and oval.
1 modified-release tablet contains 500 mg clarithromycin.
Granules for oral suspension: White to off-white granules for reconstitution.
Each 5 ml of the granules for suspension contains 125 mg of clarithromycin.
Excipient with known effect: sucrose 550 mg/ml, castor oil 3.2 mg/ml.
Excipients/Inactive Ingredients: Film-coated tablet: Tablet Core: Croscarmellose Sodium, Pregelatinized Starch, Microcrystalline Cellulose, Dye Yellow (Quinoline Yellow) E104, Aluminium Lake, Silicon Dioxide, Povidone, Stearic Acid, Magnesium Stearate, Talc.
Tablet Coating, Colour and Gloss Coating: Hypromellose, Sorbitan Monooleate, Propylene Glycol, Titanium Dioxide, Vanillin, Dye Yellow (Quinoline Yellow) E104, Aluminium Lake, Hydroxypropyl cellulose, Sorbic Acid.
Modified-release tablet: Citric acid anhydrous, sodium alginate, sodium-calcium alginate, Lactose, povidone, stearic acid, magnesium stearate, talc, hypromellose, macrogol 400, macrogol 8000, titanium dioxide, Dye yellow (Quinoline Yellow) E104, Aluminum Lake, sorbic acid.
Granules for oral suspension: Granule component and coating: Carbomers, Povidone, Hypromellose phthalate, Castor Oil.
Other ingredients: Silicon dioxide, Sucrose, Xanthan gum, Flavour - fruit punch, Potassium sorbate, Citric acid, Titanium dioxide, Maltodextrin.

Pharmacotherapeutic group: Antibacterial for systemic use, macrolide. ATC Code: J01FA09.
Pharmacology: Pharmacodynamics: Film-coated tablet and Granules for oral suspension: Mechanism/Mode of action: Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts its antibacterial action by selectively binding to the 50s ribosomal sub-unit of susceptible bacteria preventing translocation of activated amino acids. It inhibits the intracellular protein synthesis of susceptible bacteria.
The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including Mycobacterium spp. An exception is Haemophilus influenza where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Clarithromycin is also bactericidal against several bacterial strains.
Clarithromycin is usually active against the following organisms in vitro: Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae, Chlamydia pneumoniae (Granules for oral suspension).
Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin also has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter species.
Breakpoints: The following breakpoints have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST). (See Table 1.)

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Modified-release tablet: Mode of action: The mechanism of action of clarithromycin is based on the inhibition of protein biosynthesis by binging to the 50S subunit of the bacterial ribosome. Clarithromycin has a relevant bactericidal effect. This is very well documented in particular for respiratory tract pathogens.
The 14(R)-hydroxy metabolite of clarithromycin, a product of the metabolisation of the parent substance which is found in humans, also has an antibacterial effect. The MICs of this metabolite are one or two-fold more active against Haemophilus influenza than the parent compound. Depending on the nature of the assay strain investigated, clarithromycin and its metabolite show an additive or synergistic effect in vitro and in vivo.
Pharmacokinetic/pharmacodynamic relationship: In recent in-vitro and in-vivo studies, it could be demonstrated that the bactericidal activity of clarithromycin is predominantly concentration-dependent. Clarithromycin is actively enriched with high concentrations of phagocytes. In vivo, the post-antibiotic effect is 2-3 times stronger than in erythromycin
Clarithromycin and the 14(R)-hydroxy clarithromycin metabolite are extremely well distributed in the body tissues and fluids. A tissue penetration study with extended-release clarithromycin confirmed that therapeutic levels of clarithromycin and its active metabolites were evident in the tissues up to 24 hours after the administration of a single daily dose of 1000 mg, essentially in the case of lower respiratory tract infections.
Following the administration of extended-release clarithromycin, at a single daily dose of 1000 mg, a higher steady state of clarithromycin concentrations were detected in the epithelial fluid (4 to 25 times higher on average) and alveolar macrophages (150-250 times higher on average) compared with plasma concentrations measured at the same time, in the 24-hour period following administration. Furthermore, 14(R)-hydroxy clarithromycin reached higher steady-state concentrations (40-80 times higher on average) in the alveolar macrophages compared to plasma concentrations.
Concentrations of the extended-release clarithromycin formulation following daily administration of 500 mg or 1000 mg reached levels in the plasma and lung tissue that exceeded the MICs of the most common pathogens in respiratory tract, skin and soft tissue infections. These concentrations were similar to the values recorded for the rapid-release pharmaceutical form.
Mechanism of resistance: Resistance to clarithromycin can be based on the following mechanisms: Efflux: resistance can be caused as a result of an increase in the number of efflux pumps in the cytoplasmic membrane, by which only 14- and 15- membered macrolides are affected (so-called M phenotype).
Change in the target structure: as a result of the methylation of the 23S rRNS, the affinity for the ribosomal binding sites is reduced, resulting in resistance to macrolides (M), lincosamides (L) and group B streptogramins (S_B) (so-called MLS_B phenotype).
The enzymatic inactivation of macrolides is only of subordinate clinical importance.
In the M phenotype, there is complete cross-resistance of clarithromycin with azithromycin, erythromycin and roxithromycin. In the MLS_B phenotype, there is additionally cross-resistance with clindamycin and streptogramin B. There is partial cross-resistance with the 16-membered macrolide spiramycin.
Breakpoints: Clarithromycin is tested using the usual serial dilution. The following minimal inhibitory concentrations are established for susceptible and resistant micro-organisms: EUCAST (European Committee on Antimicrobial Susceptibility Testing): See Table 2.

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Prevalence of acquired resistance in Germany: The prevalence of acquired resistance of individual species can vary from place to place and over time. Therefore, particularly for adequate treatment of severe infections, local information on the resistance situation is required. If, because of the local resistance situations, the efficacy of clarithromycin is called into question, a therapy consultation by experts should be sought. Particularly in serious infections or in the case of failed therapy, a microbiological diagnosis with detection of the microorganisms and their susceptibility to clarithromycin should be sought. However, it has not been definitively proven that in vitro resistance leads to clinical inefficacy in the case of mild to moderately severe community-acquired respiratory tract infections.
Prevalence of acquired resistance in Germany on the basis of the data of the last 5 years from national resistance-monitoring projects and studies (status: February 2018): See Table 3.

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Pharmacokinetics: Film-coated tablet: H. pylori is associated with acid peptic disease including duodenal ulcer and gastric ulcer in which about 95% and 80% of patients respectively are infected with the agent. H. pylori is also implicated as a major contribution factor in the development of gastritis and ulcer recurrence in such patients.
Clarithromycin has been used in small numbers of patients in other treatment regimens. Possible kinetic interactions have not been fully investigated. These regimens include: Clarithromycin plus tinidazole and omeprazole; clarithromycin plus tetracycline, bismuth subsalicylate and ranitidine; clarithromycin plus ranitidine alone.
Clinical studies using various different H. pylori eradication regimens have shown that eradication of H. pylori prevents ulcer recurrence.
Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration of Clarithromycin tablets. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability of Clarithromycin tablets. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxymetabolite.
The pharmacokinetics of clarithromycin are non linear; however, steady-state is attained within 2 days of dosing. At 250 mg b.i.d. 15-20% of unchanged drug is excreted in the urine. With 500 mg b.i.d. daily dosing urinary excretion is greater (approximately 36%). The 14-hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of the parent drug is recovered from the faeces.
When clarithromycin 500 mg is given three times daily, the clarithromycin plasma concentrations are increased with respect to the 500 mg twice daily dosage.
Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Clarithromycin also penetrates the gastric mucus. Levels of clarithromycin in gastric mucus and gastric tissue are higher when clarithromycin is co-administered with omeprazole than when clarithromycin is administered alone.
Modified-release tablet: Absorption: Clarithromycin is less sensitive to gastric acid than erythromycin due to its structure as 6-O-methyl erythromycin.
Extended-release clarithromycin tablets facilitate the absorption of clarithromycin via the gastrointestinal tract over 12 to 14 hours after oral administration. Compared to an equivalent dose of fast-releasing clarithromycin tablets, the extended-release tablets reach lower and later maximum steady-state plasma concentrations but an equivalent 24-hour AUC for clarithromycin and its microbiologically active metabolites, 14(R)-hydroxy clarithromycin. The AUC values at time zero (prior to administration) up to 3 hours post-dose (AUC_0-3) were higher for rapid-release clarithromycin, taken twice daily, than for the same single daily dose of extended-release clarithromycin. This shows that there is no risk of a rapid decrease in plasma levels with the extended-release pharmaceutical form.
The pharmacokinetic profile of orally administered rapid-release clarithromycin has been studied extensively in numerous studies in humans and animals. These studies show that clarithromycin is absorbed effectively and rapidly with an absolute bioavailability of almost 50%. Small or no unexpected accumulations were found.
Bioequivalence studies comparing rapid and extended-release pharmaceutical forms highlighted a relative bioavailability of almost 96% for clarithromycin and 100% for 14(R)-hydroxy clarithromycin.
Whereas the extent of 14(R)-hydroxy clarithromycin formulation is not affected by food intake following administration of Klacid MR tablets (1000 mg once daily). Administration on an empty stomach compared to administration with food is linked to an approximately 30% lower AUC for clarithromycin. Therefore, Klacid MR should be taken with food.
Pharmacokinetic study data: The absorption of clarithromycin in the gastrointestinal tract following oral administration is delayed with Klacid MR Tablets. Compared to an equivalent daily dose with rapid-release clarithromycin tablets, the extended-release tablets lead to lower, later maximum steady state plasma concentrations but an equivalent 24-hour AUC for clarithromycin and its microbiologically active metabolites, 14(R)-hydroxy clarithromycin.
Summary of the pharmacokinetic results recorded for clarithromycin and 14(R)-hydroxy clarithromycin: See Table 4.

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In a repeated dose study, the uniform mean half-life for extended-release clarithromycin (5.6; 5.7 hours) compared to rapid-release clarithromycin (5.3 hours) was slightly increased but the differences were not statistically significant. The established half-life is initially determined by the intrinsic elimination half-life of the substance, clarithromycin. This is anticipated, regardless of pharmaceutical form.
Distribution: Clarithromycin and the 14(R)-hydroxy clarithromycin metabolite are very well distributed in the body tissues and body fluids. The distribution volume is approximately 2 to 4 l/kg (see Pharmacodynamics as previously mentioned). In-vitro studies with clarithromycin revealed average plasma protein binding of 70% with concentrations of 0.45 to 4.5 μg/ml.
Macrolides penetrate the phagocytes (polynuclear neutrophils, monocytes, peritoneal and alveolar macrophages) where they accumulate. The intraphagocytic concentrations in humans can be high. These properties account for the efficacy of clarithromycin against intracellular bacteria.
One study with Klacid MR administered at a single daily dose of 2 x 500 mg for 5 days showed that the concentration of clarithromycin and its active metabolites was higher in the epithelial fluid (4 to 25 times higher on average) and the alveolar macrophages (150 to 250 times higher on average) than in the plasma.
Metabolism: The data currently available show that clarithromycin is primarily metabolized at cytochrome-P450 3A (CYP3A) in the liver. Clarithromycin is extensively metabolized essentially via N-demethylation or oxidation in position 14 of the molecule. Hydroxylation at position C-14 is stereospecific. Clarithromycin is biologically converted into three metabolites, namely N-demethyl-clarithromycin, descladinosyl-clarithromycin and 14-OH-clarithromycin.
The most important metabolite in humans and other primates is the microbiologically active metabolite, 14-OH-clarithromycin. This metabolite is as active as or 1 to 2 times less active than the parent compound against most organisms, except for H. influenza, against which it is 1 to 2 times more active. Depending on the strain, the mother compound and the 14-OH metabolite have an additive or synergistic effect on H. influenza both in vitro and in vivo.
Non-linearity: The non-linear pharmacokinetic profile of clarithromycin, combined with the relative decrease in 14-hydroxylation and N-demethylation at higher doses, shows that the metabolism of clarithromycin reaches saturation at high doses. Non-linearity is slight with a clinically relevant daily dose of 1000 mg or less.
Elimination: Clarithromycin is eliminated via the liver and kidneys. Measurements recorded with radio-labelled substance in humans following single oral dose administration of 250 mg or 1200 mg rapid-release clarithromycin showed that the amount excreted via the urine accounted for 37.9% of the lower dose and 46% of the higher dose. The parent compound (18.4% and 29.4%) and the 14-(R)-hydroxy clarithromycin metabolite (13.7% and 9.9%) account for the majority eliminated in radioactive urine following the administration of 250 mg and 1200 mg, respectively.
As regards elimination in the stools, 40.2% (250 mg dose) and 29.1% (1200 mg dose) were detected. The parent compound accounted for 4.4% and 10.6%, respectively, equivalent to the low and high doses. A comparison of the metabolite profile in the stools and urine showed that the second metabolisation products are mainly eliminated in the stools.
Hepatic Impairment: No changes in the pharmacokinetic data of clarithromycin and the 14-(R)-hydroxy metabolite were observed in patients with mild, alcohol-induced liver damage. No studies have been carried out in subjects with severe hepatic impairment.
Renal Impairment: A study involving healthy subjects presenting with impaired renal function was carried out in order to assess and compare the pharmacokinetic profile of multiple dosing with 500 mg rapid-release clarithromycin. The plasma levels, half-life, C_max and C_min for clarithromycin and its 14-(R)-hydroxy metabolite were higher and the AUC was greater in subjects with impaired renal function. The elimination constant (K_elim) and elimination via the urine were lower.
Most pharmacokinetic parameters show a clear correlation with creatinine clearance. When creatinine clearance is less than 30 ml/minute, the elimination half-life is tripled for clarithromycin and quadrupled for 14-OH-clarithromycin, which indicates significantly higher accumulation. After 5 days of treatment, a C_max of 8.3 μg/ml was recorded in patients with severe renal failure (creatinine clearance of 10 to 29 ml/min). Similar changes were observed in the kinetic profile of the 14-(R)-hydroxy clarithromycin metabolite.
Elderly patients: A study involving elderly male and female subjects (age >65) and young male subjects (21-29 years) was carried out in order to assess and compare multiple dosing safety and the pharmacokinetic profile of 500 mg rapid-release clarithromycin. Higher plasma levels and slower elimination were recorded with the parent compound and 14-(R)-hydroxy clarithromycin metabolite in the elderly test group than in the younger test group. The differences could be linked to the physiological decrease in kidney function in older patients.
No difference was, however, observed between the groups when a correlation was established between renal clearance and creatinine clearance. These results indicate that the onset of metabolisation effects with clarithromycin is linked to renal function as opposed to age.
Granules for oral suspension: Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration. The microbiologically active 14(R)-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin, may be given without regard to meals as food does not affect the extent of bioavailability. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite. Although the pharmacokinetics of clarithromycin are non linear, steady state is attained within 2 days of dosing. 14-Hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of the parent drug is recovered from the faeces.
Clarithromycin provides tissue concentrations that are several times higher than circulating drug level. Increased levels of clarithromycin have been found in both tonsillar and lung tissue. Clarithromycin penetrates into the middle ear fluid at concentrations greater than in the serum. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Klacid granules for oral susp 125 mg/5 ml does not contain tartrazine or other azo dyes, lactose or gluten.
Toxicology: Preclinical safety data: Film-coated tablet and Granules for oral suspension: Fertility, Reproduction and Teratogenicity: Studies performed in rats at oral doses up to 500 mg/kg/day (highest dose associated with overt renal toxicity) demonstrated no evidence for clarithromycin-related adverse effects on male fertility. This dose corresponds to a human equivalent dose (HED) of approximately 5 times the maximum recommended human dose (MRHD) on a mg/m² basis for a 60-kg individual.
Fertility and reproduction studies in female rats have shown that a daily dosage of 150 mg/kg/day (highest dose tested) caused no adverse effects on the oestrus cycle, fertility, parturition and number and viability of offspring. Oral teratogenicity studies in rats (Wistar and Sprague-Dawley), rabbits (New Zealand White) and cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin at the highest doses tested up to 1.5, 2.4 and 1.5 times the MRHD on a mg/m² basis in the respective species. However, a similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate at ~5 times the MRHD on a mg/m² basis for a 60-kg individual. Embryonic loss was seen in monkeys but only at dose levels which were clearly toxic to the mothers.
Film-coated tablet: In acute mouse and rat studies, the median lethal dose was greater than the highest feasible dose for administration (5 g/kg).
In repeated dose studies, toxicity was related to dose, duration of treatment and species. Dogs were more sensitive than primates or rats. The major clinical signs at toxic doses included emesis, weakness, reduced food consumption and weight gain, salivation, dehydration and hyperactivity. In all species the liver was the primary target organ at toxic doses. Hepatotoxicity was detectable by early elevations of liver function tests. Discontinuation of the drug generally resulted in a return to or toward normal results. Other tissues less commonly affected included the stomach, thymus and other lymphoid tissues and the kidneys. At near therapeutic doses, conjunctival injection and lacrimation occurred only in dogs. At a massive dose of 400 mg/kg/day, some dogs and monkeys developed corneal opacities and/or oedema.
Modified-release tablet: Animal studies showed that the toxicity of clarithromycin depends on the dose and duration of the treatment. In all species, the liver was the target organ of toxic effects; in dogs and monkeys, lesions were detectable in the liver after a 14-day treatment. However, the toxic doses in animals were clearly higher than the recommended therapeutic doses in humans. In rats treated with 150 mg/kg/day of clarithromycin, cardiovascular deformities were evident.
In-vitro and in-vivo studies on the mutagenic potential were negative.
Reproductive toxicity studies showed that clarithromycin in maternally-toxic doses in rabbits and monkeys leads to increased miscarriage. In studies on rats, no embryotoxicity or teratogenicity was established. In mice, at 70 times the clinical dose cleft palate occurred (frequency 3 to 30%).
Granules for oral suspension: The acute oral LD₅₀ values for a clarithromycin suspension administered to 3-day old mice were 1290 mg/kg for males and 1230 mg/kg for females. The LD₅₀ values in 3-day old rats were 1330 mg/kg for males and 1270 mg/kg for females. For comparison, the LD₅₀ of 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 behaviour 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 depressed suckling behaviour or bleeding from the intestines.
Pre-weaning rats (5 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 haemoglobin and haematocrit 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 (granules for suspension) for 6 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 1 to 2 hours after administration during the last 3 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, 3 weeks of age, were treated orally daily for four weeks with 0, 30, 100, or 300 mg/kg of clarithromycin, followed by a 4-week recovery period. No deaths occurred and no changed 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.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Film-coated tablet: Klacid Tab 250 mg are indicated in adults and children 12 years and older.
Clarithromycin is indicated for treatment of infections caused by susceptible organisms. Indications include: Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Upper respiratory tract infections for example, sinusitis and pharyngitis.
Clarithromycin is appropriate for initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens.
Clarithromycin is also indicated in skin and soft tissue infections of mild to moderate severity (e.g. folliculitis, cellulitis, erysipelas) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Clarithromycin in the presence of acid suppression effected by omeprazole or lansoprazole is also indicated for the eradication of H. pylori in patients with duodenal ulcers. See Dosage & Administration.
Clarithromycin is usually active against the following organisms in vitro: Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-haemolytic streptococci); alpha-haemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae.
Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; H. pylori and Campylobacter spp.
The activity of clarithromycin against H. pylori is greater at neutral pH than at acid pH.
Modified-release tablet: Klacid MR tablet is indicated for treatment of: Lower respiratory tract infections (e.g., bronchitis, pneumonia); Upper respiratory tract infections (e.g., pharyngitis, sinusitis); and Skin and soft tissue infections (e.g., folliculitis, cellulitis, erysipelas).
Granules for oral suspension: Klacid Granules for Oral Susp 125 mg/5 ml is indicated in children 6 months to 12 years.
Klacid Granules for Oral Susp 125 mg/5 ml is indicated for treatment of infections caused by susceptible organisms. Indications include: Lower respiratory tract infections (e.g. bronchitis, pneumonia) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing); Upper respiratory tract infections (e.g. pharyngitis, sinusitis); Skin and soft tissue infections (e.g. folliculitis, cellulitis, erysipelas) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing); Acute otitis media.

Film-coated tablet: Patients with respiratory tract/skin and soft tissue infections: Adults: The usual dose is 250 mg twice daily although this may be increased to 500 mg twice daily in severe infections. The usual duration of treatment is 6 to 14 days.
Children older than 12 years: As for adults.
Children younger than 12 years: Use of Klacid Tab 250 mg are not recommended for children younger than 12 years. Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension (granules for oral suspension).
Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability.
Eradication of H. pylori in patients with duodenal ulcers (Adults): The usual duration of treatment is 6 to 14 days.
Triple Therapy: Clarithromycin (500 mg) twice daily and lansoprazole 30 mg twice daily should be given with amoxycillin 1000 mg twice daily.
Triple Therapy: Clarithromycin (500 mg) twice daily and lansoprazole 30 mg twice daily should be given with metronidazole 400 mg twice daily.
Triple Therapy: Clarithromycin (500 mg) twice daily and omeprazole 40 mg daily should be given with amoxycillin 1000 mg twice daily or metronidazole 400 mg twice daily.
Triple Therapy: Clarithromycin (500 mg) twice daily and omeprazole 20 mg daily should be given with amoxycillin 1000 mg twice daily.
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.
Modified-release tablet: Adults: The usual recommended dosage of Klacid MR tablet in adults 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 Klacid MR tablet.
Pediatric: The use of Klacid MR tablet has not been studied in children less than 12 years of age.
Patients with 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 500 mg modified-release tablet once daily.
No dose adjustment is required for patients with moderate renal impairment (creatinine clearance 30 to 60 ml/min).
The usual duration of treatment is 6 to 14 days. Treatment should not be continued beyond 14 days in these patients.
Patients with impaired hepatic function: Clarithromycin is eliminated mainly via the liver. Patients with severely impaired hepatic function should not be treated with Klacid MR tablets until further clinical experience is available.
Patients treated concomitantly with ritonavir and with: A normal renal function: Dose reduction is not required in patients with normal renal function. However, the daily dose of 1000 mg clarithromycin (equivalent to 2 Klacid MR tablets) should not be exceeded.
Limited renal function (creatinine clearance 30 to 60 ml/min): In patients with a creatinine clearance of 30 to 60 ml/min who are taking Ritonavir concomitantly, the dose level of clarithromycin should be reduced by 50% so that a maximum daily dose of 500 mg clarithromycin (equivalent to 1 Klacid MR tablet) is not exceeded.
Severely impaired renal function (creatinine clearance <30 ml/min): No appropriate dose reduction is feasible in patients with a clearance <30 ml/min who are taking ritonavir concomitantly*.
*Klacid MR tablets cannot be divided. If a dose is reduced to less than 500 mg clarithromycin, other pharmaceutical forms with a lower active substance content are available for these patients.
Elderly patients: Follow the adult dosing instruction if no serious renal impairment is apparent (creatinine clearance <30 ml/min).
Children: Klacid MR has not been tested in patients under 12 years.
Children under 12 years: this medicinal product is not recommended for children under 12 years. An oral suspension of clarithromycin should be used for administration in children.
Children over 12 years: as for adults.
Method of administration: Klacid MR tablets must be taken at the same time every day. The medicinal product should be taken with food and sufficient fluid intake, e.g. a glass of water.
Granules for oral suspension: Pediatric Patients under 12 years of age: Clinical trials have been conducted using Klacid Granules for Oral Susp 125 mg/5 ml in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Klacid Granules for Oral Susp 125 mg/5 ml.
Recommended doses and dosage schedules: The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. The recommended daily dosage of Klacid Granules for Oral Susp 125 mg/5 ml in children is given in the following table and is based on a 7.5 mg/kg b.i.d. dosing regime up to a maximum dose of 500 mg b.i.d. The prepared suspension can be taken with or without meals and can be taken with milk.
Klacid Granules for Oral Susp 125 mg/5 ml Dosage in Children: See Table 5.

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Renal impairment: In children with creatinine clearance less than 30 ml/min/1.73 m², the dosage of clarithromycin should be reduced by half to 7.5 mg/kg per day.
Dosage should not be continued beyond 14 days in these patients.
Preparation for use: see Special precautions for disposal and other handling under Cautions for Usage.

Film-coated tablet and Granules for oral suspension: Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia.
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 haemodialysis or peritoneal dialysis.
Modified-release tablet: An overdose of clarithromycin generally produces gastrointestinal symptoms.
Gastric lavage should be considered within the first two hours of ingestion. Clarithromycin cannot undergo adequate haemodialysis or peritoneal dialysis. Absorption-preventing measures are recommended.
One patient who had a history of bipolar disorder ingested 8 g of clarithromycin in a suicide attempt which resulted in paranoid behavior and altered mental status, as well as hypokalemia and mild hypoxemia.

Hypersensitivity to macrolide antibiotic drugs/agents or to any of the excipients listed in Description.
Concomitant administration of clarithromycin and ergot alkaloids/ergotamine derivatives (e.g., ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see Precautions and Interactions).
Concomitant administration of clarithromycin and oral midazolam is contraindicated (see Interactions).
Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, domperidone, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see Precautions and 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).
Concomitant administration with ticagrelor or ranolazine is contraindicated.
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 Interactions).
As with other strong CYP3A4 inhibitors, Clarithromycin should not be used in patients taking colchicine (see Precautions and Interactions).
Clarithromycin should not be given to/taken by patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of the QT interval/time).
Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.
Film-coated tablet and Granules for oral suspension: Concomitant administration of clarithromycin and lomitapide is contraindicated (see Interactions).

Film-coated tablet and Granules for oral suspension: The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see Use in Pregnancy & Lactation).
Clarithromycin is principally metabolised by the liver. Therefore, caution should be exercised in administering this antibiotic to patients with impaired hepatic function.
Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment (see Dosage & Administration).
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. Cases of fatal hepatic failure (see Adverse Reactions) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, 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.
Clostridioides difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea 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 diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of clarithromycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.
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: Prolongation of the QT interval, reflecting effects on cardiac repolarisation imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in patients treated with macrolides including clarithromycin (see Adverse Reactions). Due to increased risk of QT prolongation and ventricular arrhythmias (including torsades de pointes), the use of clarithromycin is contraindicated in patients taking any of astemizole, cisapride, domperidone, pimozide and terfenadine; in patients who have electrolyte disturbances such as hypomagnesaemia or hypokalaemia; and in patients with a history of QT prolongation or ventricular cardiac arrhythmia (see Contraindications).
Carefully consider the balance of benefits and risks before prescribing clarithromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see Interactions).
Furthermore, clarithromycin should be used with caution in the following: Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia; Patients concomitantly taking other medicinal products associated with QT prolongation other than those which are contraindicated.
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 generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS)), 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).
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 hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylureas) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended (see Interactions).
Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see Interactions). 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).
Long-term use may, as with other antibiotics, result in colonisation with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.
Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.
Excipients: Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take Klacid granules for oral susp 125 mg/5 ml. When prescribing to diabetic patients, the sucrose content should be taken into account.
Film-coated tablet: Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.
Modified-release tablet: The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy (see Use in Pregnancy & Lactation).
Patients with hepatic function disorders: Clarithromycin is principally metabolized by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. In patients with suspected hepatic function disorders, the serum concentrations of transaminases (AST, ALT), γ-GT and alkaline phosphatase, as well as serum bilirubin, should be carefully monitored (see Contraindications).
Hepatic function disorders, including elevated liver enzymes values, and hepatocellular damage and/or cholestatic hepatitis with or without jaundice, have been reported in connection with clarithromycin. This hepatic function disorder may be severe but is usually reversible. In some cases, hepatic failure with fatal outcome has been reported, which was associated with serious underlying diseases and/or other hepatotoxic medications. Discontinue using clarithromycin immediately if signs and symptoms of hepatitis such as anorexia, jaundice, dark urine, pruritus, or tender abdomen occur.
Patients with renal function disorders: Caution is advised in patients with severe renal impairment. If severe renal impairment exists (creatinine clearance <30 ml/min), this medicinal product should be used only under close medical supervision (see Dosage & Administration).
When taking other macrolide antibiotics as well as lincomycin and clindamycin: Attention should be paid to the possibility of cross-resistance of pathogens to clarithromycin and other macrolide antibiotics (e.g. erythromycin), as well as lincomycin and clindamycin. Concomitant administration of several preparations from this substance group therefore seems inadvisable.
Colchicine: There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly. Some of the colchicine toxicity occurred in patients with renal function disorders. Deaths have been reported in some of 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: Prolongation of the QT interval has been observed in patients treated with macrolides including clarithromycin, which reflects cardiac repolarization. This is associated with the risk of developing cardiac arrhythmia and torsades de pointes (see Adverse Reactions). Given the increased risk of prolongation of QT intervals and ventricular arrhythmias (including torsade de pointes), clarithromycin is contraindicated in patients taking astemizole, cisapride, domperidone, pimozide and terfenadine, in patients with hypokalaemia and in those with a history of prolongation of the QT interval or ventricular arrhythmia (see Contraindications).
Clarithromycin should be used with caution in the following patients: Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia; Patients with hypomagnesaemia; Patients concomitantly taking other medicinal products which prolong the QT interval and are contraindicated as such.
Epidemiological studies to assess the risk of adverse cardiovascular reactions following administration of macrolides have highlighted various results. A rare, short-term risk of arrhythmias, myocardial infarction and cardiovascular mortality has been noted during some observational studies following administration of macrolides including clarithromycin. These correlations should be considered in the benefit-risk context when prescribing clarithromycin.
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. because of allergies), other antibiotics, such as clindamycin, may be the drugs 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 cases where penicillin treatment cannot be used.
In the case 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 and drug reaction with eosinophilia and systemic symptoms [DRESS syndrome], clarithromycin treatment should be discontinued immediately and appropriate treatment should be urgently initiated.
Persistent and severe diarrhoea and colic: Like almost all antibacterial agents including macrolides, pseudomembranous colitis has been reported, which may range from mild to life-threatening. Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibiotics, including clarithromycin, which can occur in the form of mild diarrhoea progressing to fatal colitis. Treatment with antibiotics alters the normal flora of the colon, which may lead to overgrowth of C. difficile. Therefore, in patients with diarrhoea which occurred during or following therapy with antibacterial agents, CDAD must be considered. CDAD may also occur 2 months after the end of the therapy. A careful medical history is therefore necessary.
Depending on the indication, discontinuation of Klacid MR therapy should be considered and, if necessary, appropriate treatment should be initiated immediately (e.g. appropriate antibiotics/chemotherapeutic agents, the clinical efficacy of which has been established in these indications). Drugs that inhibit peristalsis should not be used.
Long-term use may, as with other antibiotics, result in colonization with non-susceptible bacteria and fungi. If a superinfection occurs, appropriate therapy should be instituted.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see Interactions).
Oral antidiabetic agents/Insulin: Concomitant administration of clarithromycin and oral hypoglycemic agents (such as sulphonylureas) and/or insulin can result in significant hypoglycemia. Careful monitoring of blood glucose level is recommended (see Interactions).
Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations of the INR values and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be regularly monitored while patients are taking clarithromycin and oral anticoagulants concurrently.
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 statins at the same time. Rhabdomyolysis have been reported in patients taking clarithromycin and statins concomitantly. Patients should be monitored for signs and symptoms of myopathy.
In cases where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest permitted dose of the statin. Use of another statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see Interactions).
Patients with rare hereditary galactose intolerance, lactase deficiency or glucose-galactose-malabsorption should not take Klacid MR.
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.

Film-coated tablet and Granules for oral suspension: Pregnancy: The safety of clarithromycin for use during pregnancy has not been established. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal 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 with use of macrolides including clarithromycin during pregnancy provide conflicting results.
Therefore, use during pregnancy is not advised without carefully weighing the benefits against risks (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Breast-feeding: The safety of clarithromycin for using during breast-feeding of infants has not been established. 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 the maternal weight-adjusted dose of clarithromycin.
Fertility: In the rat, fertility studies have not shown any evidence of harmful effects (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Modified-release tablet: Pregnancy: Data on clarithromycin use during the first trimester of a limited number of pregnancies showed no clear evidence of teratogenic effects or any other harmful effects on the neonate. At present there are no other relevant epidemiological data available. Results from animal studies showed reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The risk for humans is not shown. Clarithromycin should be used during pregnancy, especially in the first trimester, only when strictly indicated.
Lactation: Clarithromycin and its active metabolite pass into breastmilk. In breast-fed infants, this may cause changes in the intestinal flora with diarrhoea and colonization with yeast-like fungi, so that breast-feeding may need to be interrupted. The possibility of sensitization should also be considered. In breastfeeding women, using the treatment for the mother should be weighed carefully against the potential risk to the child.
Fertility: Fertility studies in rats have not revealed any harmful effects.

Summary of the safety profile: The most frequent and common adverse reactions related to clarithromycin therapy for both adult and adolescents/paediatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see Tabulated summary of adverse reactions as follows).
There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without pre-existing mycobacterial infections.
Tabulated summary of adverse reactions: Film-coated tablet and Granules for oral suspension: The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets.
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.)

Click on icon to see table/diagram/image

Modified-release tablet: The following table takes into account all adverse reactions reported in clinical studies and from post-marketing experience with clarithromycin forms and strengths.
When evaluating undesirable effects that are at least possibly associated with clarithromycin, the following frequencies are taken as a basis: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data). Within each frequency grouping, the adverse reactions are, if possible, presented in decreasing order of significance.
Undesirable events associated with clarithromycin: See Table 7.

Click on icon to see table/diagram/image

Description of selected adverse reactions: Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation/pharmaceutical form.
In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see Contraindications and Precautions).
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/recommended (see Interactions).
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 diarrhoea. 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.
Special population: Adverse Reactions in Immunocompromised Patients (see Other special populations as follows).
Modified-release tablet: Residues of Klacid MR tablets in stools: Residues of Klacid MR tablets have very occasionally been reported in patients with anatomical (including ileostomy or colostomy) or functional disorders of the gastrointestinal tract with a shorter GI transit time. There have been some reports of tablet residues in conjunction with diarrhoea. Patients presenting with tablet residues in stools and whose condition does not appear to have improved should be switched to another clarithromycin formulation (e.g. suspension) or another antibiotic.
Paediatric populations (Children and adolescents): Clinical trials have been conducted using clarithromycin paediatric suspension (Klacid Granules for Oral Susp 125 mg/5 ml) in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension (Klacid Granules for Oral Susp 125 mg/5 ml).
Frequency, type and degree of severity of adverse reactions in children are expected to be the same as in adults.
Other special populations: 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 Human Immunodeficiency Virus (HIV) disease or intercurrent illness.
In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1000 mg and 2000 mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1000 mg and 2000 mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000 mg of clarithromycin.
In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000 mg or 2000 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 in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000 mg daily for all parameters except White Blood Cell.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Drug Office, Department of Health via link http://www.drugoffice.gov.hk/eps/do/en/healthcare_providers/adr_reporting/adr_report_form.html4.9

Film-coated tablet and Granules for oral suspension: The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Astemizole, cisapride, domperidone, pimozide, 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 2- to 3-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: Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and ischaemia 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.
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-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 (C_min) 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 C_max increased by 31%, C_min 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%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/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: CYP3A-based interactions: Co-administration of clarithromycin, which is known to inhibit CYP3A, and a drug primarily metabolised by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.
The use of clarithromycin is contraindicated in patients receiving the CYP3A substrates astemizole, cisapride, domperidone, pimozide and terfenadine due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see Contraindications and Precautions).
The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG CoA reductase inhibitors metabolised mainly by CYP3A4 (e.g. lovastatin and simvastatin), colchicine, ticagrelor and ranolazine (see Contraindications).
Concomitant administration of clarithromycin with lomitapide is contraindicated due to the potential for markedly increased transaminases (see Contraindications).
Caution is required if clarithromycin is co-administered 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 metabolised by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin. Drugs or drug classes that are known or suspected to be metabolised by the same CYP3A isozyme include (but this list is not comprehensive) alprazolam, carbamazepine, cilostazole, ciclosporin, disopyramide, ibrutinib, methadone, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam and vinblastine.
Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.
Antiarrhythmics: There have been post-marketing reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide 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 hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.
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 (C_max, 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.
Direct acting oral anticoagulants (DOACs): The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolised 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).
Sildenafil, tadalafil and vardenafil: Each of these phosphodiesterase inhibitors is metabolised, 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 that 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. Dose reduction may need to be considered.
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 metaboliser 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. 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 metabolised 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 (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 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 paediatric 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 metabolised 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.
Hydroxychloroquine and Chloroquine: Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Because of the potential for a similar risk with other macrolides when used in combination with hydroxychloroquine or chloroquine, careful consideration should be given to the balance of benefits and risks before prescribing clarithromycin for any patients taking hydroxychloroquine or chloroquine.
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 twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and C_max values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and C_max 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 Ritonavir as previously mentioned).
Patients taking oral contraceptives should be warned that if diarrhoea, vomiting or breakthrough bleeding occur there is a possibility of contraceptive failure.
Modified-release tablet: Using/taking the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Astemizole, cisapride, domperidone, pimozide and terfenadine: Elevated cisapride levels have been reported in patients taking clarithromycin and cisapride concomitantly. This can lead to prolongation of the QT interval and arrhythmias including ventricular arrhythmia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
It has been reported that Macrolides alter the metabolism of terfenadine. This results 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 metabolite of terfenadine and in prolongation of the QT interval without any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergotamine derivatives: Postmarketing reports indicate that concomitant use of clarithromycin and dihydroergotamine or non-hydrogenated ergot alkaloids has been associated with acute toxicity, characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergotamine derivatives is contraindicated (see Contraindications).
Oral midazolam: When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), the 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. There have been reports of patients with rhabdomyolysis who received 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 and statins at the same time. In cases where the concomitant use of clarithromycin and statins cannot be avoided, it is recommended to prescribe the lowest permitted dose of the statin. Use of another statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.
Effects of other medicinal products on clarithromycin: The following drugs are known or suspected to affect the plasma concentrations of clarithromycin. Clarithromycin dosage adjustment or an alternative treatment should be considered.
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, as this may be increased owing to the inhibition of CYP3A by clarithromycin (see also the current product information for the CYP3A4 inhibitor administered). Concomitant administration of clarithromycin and rifabutin resulted in an increase in rifabutin and a decrease in clarithromycin serum levels, which again leads an increased risk of uveitis.
Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to an increase in the mean steady-state minimum clarithromycin concentration (C_min) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14(R)-hydroxy-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir: When clarithromycin is administered concomitantly with ritonavir, the systemic availability (AUC), the maximum concentration (C_max) and the minimum concentration (C_min) of clarithromycin increase. 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 impairment (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased by 75%. Other clarithromycin pharmaceutical forms with a lower active substance content are available to these patients.
When protease inhibitors are taken concomitantly, a daily dose of 1 g clarithromycin should not be exceeded (see Dosage & Administration).
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 Other possible significant pharmacokinetic interactions as follows).
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine: Strong inducers of the cytochrome P450 metabolism system, such as nevirapine, rifampicin, rifabutin, rifapentine and efavirenz, may accelerate the metabolism of clarithromycin and thus lower the plasma levels and bioavailability of clarithromycin by around 30-40%, increase those of the microbiologically active metabolite 14(R)-hydroxy clarithromycin (14-OH-clarithromycin by approximately the same amount. As the ratio of the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, when enzyme inducers and clarithromycin are administered concomitantly, it should be checked in individual cases whether the intended therapeutic effect should be impaired by this fact.
Etravirine: Clarithromycin levels were 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.
Effect of clarithromycin on other medicinal products: CYP3A-based Interactions: Concomitant administration of clarithromycin, known to inhibit CYP3A, and an active substance mainly metabolized by CYP3A may be associated with an increase in active substance concentrations, which can increase or potentiate both the therapeutic and adverse effects of the concomitant drug.
Clarithromycin is contraindicated in patients receiving the CYP3A substrates atemizole, cisapride, domperidone, pimozide and terfenadine due to the risk of prolongation of the QT interval and arrhythmias including tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications and Precautions).
The use of clarithromycin is also contraindicated with ergotamine alkaloids, oral midazolam, HMG CoA reductase inhibitors, mainly metabolized by CYP3A4 (e.g. lovastatin and simvastatin), colchicine, ticagrelor and ranolazine (see Contraindications).
Caution should be exercised if clarithromycin is administered concomitantly with other drugs known as CYP3A enzyme substrates especially if the CYP3A substrate has a narrow therapeutic spectrum (e.g., carbamazepine) and/or the substrate is largely metabolized by this enzyme. Dose adjustments may be taken into consideration and, if possible, the serum concentrations of the drugs essentially metabolized by CYP3A, should be closely monitored in patients receiving clarithromycin concomitantly.
Drugs or drug classes known or suspected to be metabolized by the same CYP3A isozyme include (but this list is not exhaustive) alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, ibrutinib, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam and vinblastine.
Drugs that interact by similar mechanisms through other isozymes of the cytochrome P450 system include phenytoin, theophylline and valproate.
Antiarrhythmics: There have been reports of torsades de pointes occurring after concurrent use of clarithromycin and quinidine or disopyramide. During concomitant administration of clarithromycin and these drugs, electrocardiograms should be monitored for QTc prolongation. Monitoring of the serum concentrations of these active substances during therapy is recommended.
There have been post-marketing reports of hypoglycaemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Oral antidiabetic agents/insulin: When using certain antidiabetic agents concomitantly, such as nateglinide and repaglinide, inhibition of the CYP3A enzyme by clarithromycin may occur and cause hypoglycaemia. Careful monitoring of blood glucose levels is recommended.
Omeprazole: Healthy adult subjects were given 500 mg clarithromycin in combination with 40 mg omeprazole every 8 hours. The steady-state plasma concentrations of omeprazole were increased with the concomitant administration of clarithromycin (maximum omeprazole concentration (C_max), systemic availability (AUC_0-24), and elimination half-life values increased by 30%, 89%, and 34%, respectively). 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: All of these phosphodiesterase inhibitors are metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. It has been reported that erythromycin increases the systemic availability (area under the curve, AUC) of sildenafil. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil could possibly result in an increase in the phosphodiesterase inhibitors.
In one study in which vardenafil was co-administered with erythromycin (500 mg three times daily), a quadrupling of the vardenafil AUC and a tripling of the maximum vardenafil concentration (C_max) was observed.
Sildenafil, tadalafil and vardenafil dosages need to be reduced when co-administered with clarithromycin.
Theophylline, carbamazepine: During the therapy with clarithromycin, the metabolism of theophylline or carbamazepine may be inhibited. As a result of this, an increase in the serum concentration of theophylline or carbamazepine is possible and a dose reduction may need to be considered.
Tolterodine: The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the Caucasian population devoid of CYP2D6, metabolism is mainly via CYP3A. In this population, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in the tolterodine dosage may be necessary in the case of slow metabolism with CYP2D6 deficiency in the presence of CYP3A inhibitors such as clarithromycin.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam): When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), the midazolam AUC was increased 2.7-fold after intravenous administration. If, during the clarithromycin therapy, intravenous midazolam is also administered, the patient should be closely monitored so that the dose can be adjusted if necessary.
Administration of midazolam via the oral mucosa could bypass pre-systemic elimination of the drug and will probably result in interactions similar to those observed after intravenous rather than oral administration.
The same precautions also apply during administration of other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not metabolized by CYP3A (temazepam, nitrazepam, lorazepam), an interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Therefore, monitoring the patient for increased CNS pharmacological effects is recommended.
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 CYP3A and/or Pgp by clarithromycin may lead to increased systemic availability of colchicine. Concomitant use of clarithromycin and colchicine by patients with renal or hepatic function disorders is contraindicated (see Contraindications and Precautions).
Digoxin: Digoxin is 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 an increased digoxin serum concentration. Elevated digoxin serum levels have also been reported post-marketing in patients who received clarithromycin and digoxin concomitantly.
Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. The serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin concomitantly.
Zidovudine: During concomitant oral therapy with clarithromycin and zidovudine, in HIV-infected adults because of reduced intestinal adsorption, reduced serum levels of zidovudine have been detected. Therefore, in these patients a 4-hour staggered intake should be adhered to. This interaction was not observed in HIV-infected children who took clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered as a solution or infusion.
No in vivo data from human are available when describe an interaction of clarithromycin with the following drugs: aprepitant, eletriptan, halofantrine and ziprasidone. However, in vitro data indicate that these drugs are CYP3A substrates, therefore caution is advised when these are used concomitantly with clarithromycin.
Other drugs for which there are spontaneous reports or publications concerning an interaction with clarithromycin: CYP3A-based interactions: There have been reports on interactions of erythromycin and/or clarithromycin with bromocriptine, cyclosporine, tacrolimus, rifabutin, methylprednisolone, vinblastine and cilostazol, which are metabolized via CYP3A.
Concomitant administration of erythromycin or clarithromycin with a drug that is metabolized mainly via CYP3A may be associated with the increase in drug concentrations that potentiate or prolong both the therapeutic and the undesired effects of the co-medication. A dose adjustment should be considered and, if possible, the serum concentrations of the drugs metabolised mainly via CYP3A should be closely monitored in patients who received erythromycin or clarithromycin concomitantly.
Non-CYP3A-based interactions: Phenytoin and valproate: There have also been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin, with drugs which are not known to be metabolized by CYP3A (e.g. phenytoin, valproate and hexobarbital). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Other possible significant pharmacokinetic interactions: Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of bi-directional drug interactions. 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(R)-hydroxy 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. In the case of moderate renal impairment (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 appropriate pharmaceutical forms.
The maximum daily dose of 1000 mg clarithromycin when taken with protease inhibitors should not be exceeded (see Dosage & Administration).
For indications that are not based on infections caused by the Mycobacterium avium complex, an alternative therapy should be considered.
Patients who are taking atazanavir and clarithromycin concomitantly should be monitored for signs or symptoms of increased or prolonged pharmacological effect.
Calcium channel blockers: Because of the risk of hypotension, caution is advised in patients taking clarithromycin and calcium channel blockers that are metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem). Plasma concentrations of clarithromycin and of calcium channel blockers may be increased owing to interactions. 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 and there is evidence of bi-directional drug interactions.
Clarithromycin could increase the plasma levels of itraconazole, while itraconazole could increase the plasma levels of clarithromycin.
Regarding the effect of itraconazole and clarithromycin, a case report has been published concerning 3 patients who had higher concentrations of clarithromycin than expected when taking itraconazole concomitantly. In a small pharmacokinetic study with HIV patients, it could be shown that clarithromycin increases the plasma concentrations of itraconazole.
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 bi-directional drug interactions.
Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in system availability in the steady-state (AUC) and a maximum concentration (C_max) of saquinavir which were 177% and 187% higher than those with saquinavir alone. Clarithromycin AUC and C_max values were approximately 40% higher than those seen with clarithromycin alone. Dose adjustment is required when the two drugs are co-administered for a limited time at the strengths and in the pharmaceutical forms studied.
Observations from drug interaction studies using the soft gelatin capsules are not necessarily transferable to the use of the saquinavir hard gelatin capsule.
Observations from drug interaction studies with unboostered saquinavir are not necessarily transferable to the effects that are seen with saquinavir/ritonavir. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see Effects of other medicinal products on clarithromycin as previously mentioned).

Granules for oral suspension: Special precautions for disposal and other handling: An appropriate amount of water, should be added to the granules in the bottle and shaken to yield a reconstituted suspension. The concentration of clarithromycin in the reconstituted suspension is 125 mg per 5 mL.
Shake well before each use.
Incompatibilities: None known.

Granules for oral suspension: Klacid Granules for Oral Susp 125 mg/5 ml should be stored at room temperature (15°C to 30°C) in a well-closed container.

Macrolides

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

A