Klerimed

Clarithromycin.

Each tablet also contains the following excipients: Croscarmellose, microcrystalline cellulose, anhydrous colloidal silica, povidone, stearic acid, magnesium stearate, talc, hypromellose, propylene glycol, sorbitan, oleate, vanilla, quinolline yellow (E104), titanium dioxide (E171), hydroxy propyl cellulose and sorbic acid.

Pharmacotherapeutic Group: Antibacterial for systemic use, macrolide. ATC Code: J01FA09.
Pharmacology: Pharmacodynamics: Clarithromycin is a semi-synthetic macrolide antibiotic obtained by substitution of a CH₃O group for the hydroxyl (OH) group at position 6 of the erythromycin lactonic ring. Specifically clarithromycin is 6-O-methyl erythromycin A. The white to off-white antibiotic powder is bitter, practically odorless, essentially insoluble in water and slightly soluble in ethanol, methanol, and acetonitrile. Its molecular weight is 747.96.
Clarithromycin exerts its antibacterial action by binding to the 50s ribosomal subunit of susceptible bacteria and suppresses protein synthesis.
Clinical Studies: Helicobacter pylori is strongly associated with peptic ulcer disease. Ninety (90) to 100% of patients with duodenal ulcers are infected with this pathogen. Eradication of H. pylori has been shown to reduce the rate of duodenal ulcer recurrence, thereby reducing the need for maintenance anti-secretory therapy.
Triple Therapy in Duodenal Ulcer Disease: In a well-controlled double blind study, H. pylori-infected duodenal ulcer patients received triple therapy with clarithromycin 500 mg twice daily, amoxicillin 1,000 mg twice daily and omeprazole 20 mg daily for 10 days or dual therapy with clarithromycin 500 mg 3 times daily and omeprazole 40 mg daily for 14 days. Helicobacter pylori was eradicated in 90% of the patients receiving clarithromycin triple therapy and in 60% of the patients receiving dual therapy.
In an independent study, H. pylori-infected patients received eradication therapy with clarithromycin 500 mg twice daily in conjunction with amoxicillin 1,000 mg twice daily and omeprazole 20 mg daily (Group A) or omeprazole 20 mg twice daily (Group B) for 7 days. In those patients not previously treated with anti-H. pylori therapy, H. pylori was eradicated in 86% (95% CI = 69-95) of patients in Group A and 75% (95% CI=62-85) of patients in Group B, the difference was not statistically significant.
In an open-label study H. pylori-infected patients with duodenal ulcer or non-ulcer dyspepsia (NUD) received eradication therapy with clarithromycin 500 mg twice daily, lansoprazole 30 mg twice daily plus amoxicillin 1,000 mg twice daily for 10 days. In an all-patients-treated analysis, H. pylori was eradicated from 91% of patients.
Dual Therapy in Duodenal Ulcer Disease: In well-controlled, double-blind studies, H. pylori-infected duodenal ulcer patients received eradication therapy with clarithromycin 500 mg 3 times daily and omeprazole 40 mg daily for 14 days followed by omeprazole 40 mg (study A) or omeprazole 20 mg (studies B, C and D) daily for an additional 14 days; patients in each control group received omeprazole alone for 28 days. In study A, H. pylori was eradicated in over 80% of patients who received clarithromycin and omeprazole and in only 1% of patients receiving omeprazole alone. In studies B, C and D, the combined eradication rate was over 70% (clinically evaluable analysis) in patients receiving clarithromycin and omeprazole and <1% in patients receiving omeprazole alone. In each study, the rate of ulcer recurrence at 6 months was statistically lower in the clarithromycin and omeprazole-treated patients when compared to patients receiving omeprazole alone.
In an investigator-blind study, H. pylori-infected patients received eradication therapy with clarithromycin 500 mg three times daily in conjunction with lansoprazole 60 mg/day in single or divided doses for 14 days. The combined eradication rate was over 60%.
Pharmacokinetics: Absorption: The kinetics of orally administered clarithromycin has been studied extensively in a number of animal species and adult humans. These studies have shown clarithromycin is readily and rapidly absorbed with an absolute bioavailability of approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing. Food intake immediately before dosing increases clarithromycin bioavailability by a mean of 25%. Overall, this increase is minor and should be of little clinical significance with the recommended dosing regimens. Clarithromycin may thus be administered in either the presence or absence of food.
Distribution, Biotransformation and Elimination: In vitro: In vitro studies showed that the protein-binding of clarithromycin in human plasma averaged about 70% at concentrations of 0.45-4.5 mcg/mL. A decrease in binding to 41-45% mcg/mL suggested the binding sites might become saturated, but this only occurred at concentrations far in excess of the therapeutic drug levels.
In vivo: Results of animal studies showed clarithromycin levels in all tissues, except the central nervous system (CNS), were several times higher than the circulating drug levels. The highest concentrations were usually found in the liver and lung where the tissue to plasma (T/P) ratios reached 10-20.
Normal Subjects: With twice daily dosing at 250 mg, the peak steady-state plasma concentration was attained in 2-3 days and averaged about 1 mcg/mL for clarithromycin and 0.6 mcg/mL for 14-OH-clarithromycin, while the elimination half-lives (t_½) of the parent drug and metabolite were 3-4 hrs and 5-6 hrs, respectively. With twice daily dosing at 500 mg, the steady-state peak plasma concentration (C_max) for clarithromycin and its hydroxylated metabolite was achieved by the 5th dose. After the 5th and 7th doses, the steady-state C_max for clarithromycin averaged 2.7 and 2.9 mcg/mL; its hydroxylated metabolite averaged 0.88 and 0.83 mcg/mL, respectively. The t_½ of the parent drug at the 500-mg dose level was 4.5-4.8 hrs, while that of the 14-OH-clarithromycin was 6.9-8.7 hrs. At steady-state, the 14-OH-clarithromycin levels did not increase proportionately with the clarithromycin dose, and the apparent t_½ of both clarithromycin and its hydroxylated metabolite tended to be longer at the higher doses. This non-linear pharmacokinetic behavior of clarithromycin, coupled with the overall decrease in the formation of 14-hydroxylation and N-demethylation products at the higher doses, indicates the non-linear metabolism of clarithromycin becomes more pronounced at high doses.
In human adults given single oral doses of clarithromycin 250 or 1,200 mg, urinary excretion accounted for 37.9% of the lower dose and 46% of the higher dose. Fecal elimination accounted for 40.2% and 29.1% (this included a subject with only 1 stool sample containing 14.1%) of these respective doses.
Patients: Clarithromycin and its 14-OH metabolite distribute readily into body tissues and fluids. Limited data from a small number of patients suggests clarithromycin does not achieve significant levels in cerebrospinal fluid (CSF) after oral doses (ie, only 1-2% of serum levels in CSF in patients with normal blood-CSF barriers). Concentrations in tissues are usually several fold higher than serum concentrations. Examples from tissue and serum concentrations are presented in Table 1. (See Table 1.)

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Hepatic Impairment: In a study comparing 1 group of healthy human subjects with a group of subjects with liver impairment who were given clarithromycin 250 mg twice daily for 2 days and a single 250-mg dose, the 3rd day, steady-state plasma levels and systemic clearing of clarithromycin were not significantly different between the 2 groups. In contrast, steady-state concentrations of the 14-OH metabolite were markedly lower in the group of hepatic-impaired subjects. This decreased metabolic clearance of the parent compound by 14-hydroxylation was partially offset by an increase in the renal clearance of parent drug, resulting in comparable steady-state levels of parent drug in the hepatic-impaired and healthy subjects. These results indicate no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function.
Renal Impairment: A study was conducted to evaluate and compare the pharmacokinetic profile of multiple 500 mg oral doses of clarithromycin in subjects with normal and decreased renal function. The plasma levels, t_½, C_max and minimum plasma concentration (C_min) for both clarithromycin and its 14-OH metabolite were higher and area under the concentration-time curve (AUC) was larger in subjects with renal impairment.
K_elim and urinary excretion were lower. The extent to which these parameters differed was correlated with the degree of renal impairment; the more severe the renal impairment, the more significant the difference (see Dosage & Administration).
Elderly: A study was also conducted to evaluate and compare the safety and pharmacokinetic profiles of multiple 500-mg oral doses of clarithromycin in healthy elderly male and female subjects to those in healthy young adult male subjects. In the elderly group, circulating plasma levels were higher and elimination slower than in the younger group for both parent drug and 14-OH metabolite. However, there was no difference between the 2 groups when renal clearance was correlated with creatinine clearance. It is concluded from those results that any effect on the handling of clarithromycin is related to renal function and not to age per se.
Mycobacterium avium Infections: Steady-state concentrations of clarithromycin and 14-OH-clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hrs to adult patients with human immunodeficiency virus (HIV) infection were similar to those observed in normal subjects. However, at the higher doses which may be required to treat Mycobacterium avium infections, clarithromycin concentrations were much higher than those observed at the usual doses. In adult HIV-infected patients taking 1,000 and 2,000 mg/day in 2 divided doses, steady-state clarithromycin C_max values ranged from 2-4 mcg/mL and 5-10 mcg/mL, respectively. Elimination t_½ appeared to be lengthened at these higher doses as compared to that seen with usual doses in normal subjects. The higher plasma concentrations and longer elimination t_½ observed at these doses are consistent with the known nonlinearity in clarithromycin pharmacokinetics.
Concomitant Omeprazole Administration: A pharmacokinetic study was conducted with clarithromycin 500 mg 3 times daily and omeprazole 40 mg once-daily. When clarithromycin was given alone at 500 mg every 8 hrs, the mean steady-state C_max value was approximately 3.8 mcg/mL and the mean C_min value was approximately 1.8 mcg/mL. The mean AUC_0-8 for clarithromycin was 22.9 mcg/hr/mL. The time to reach maximum plasma concentration (T_max) and t_½ were 2.1 hr and 5.3 hr, respectively, when clarithromycin was dosed at 500 mg 3 times daily.
In the same study, when clarithromycin 500 mg 3 times daily was administered with omeprazole 40 mg once-daily, increases in omeprazole t_½ and AUC_0-24 were observed. For all subjects combined, the mean omeprazole AUC_0-24 was 89% greater and the harmonic mean for omeprazole t_½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady-state C_max, C_min, and AUC_0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively, over values achieved when clarithromycin was administered with placebo.
At steady-state, clarithromycin gastric mucous concentrations 6 hrs post-dosing were approximately 25-fold higher in the clarithromycin/omeprazole group compared with the clarithromycin alone group. Six (6) hrs post-dosing, mean clarithromycin gastric tissue concentrations were approximately 2-fold higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo.
Toxicology: Preclinical Safety Data: Acute, Subchronic and Chronic Toxicity: Studies were conducted in mice, rats, dogs and/or monkeys with clarithromycin administered orally. The duration of administration ranged from a single oral dose to repeated daily oral administration for 6 consecutive months. In acute mouse and rat studies, 1 rat, but no mice, died following a single gavage of 5 g/kg body weight. The median lethal dose, therefore, was >5 g/kg, the highest feasible dose for administration.
No adverse effects were attributed to clarithromycin in primates exposed to 100 mg/kg/day for 14 consecutive days or to 35 mg/kg/day for 1 month. Similarly, no adverse effects were seen in rats exposed to 75 mg/kg/day for 1 month, to 35 mg/kg/day for 3 months or to 8 mg/kg/day for 6 months. Dogs were more sensitive to clarithromycin, tolerating 50 mg/kg/day for 14 days, 10 mg/kg/day for 1 and 3 months, and 4 mg/kg/day for 6 months without adverse effects.
The major clinical signs at toxic doses in these studies described previously included emesis, weakness, reduced food consumption and reduced weight gain, salivation, dehydration and hyperactivity. Two (2) of 10 monkeys receiving 400 mg/kg/day died on treatment day 8; yellow discolored feces were passed on a few isolated occasions by some surviving monkeys given a dose of 400 mg/kg/day for 28 days.
The primary target organ at toxic dosages in all species was the liver. The development of hepatotoxicity in all species was detectable by early elevation of serum concentrations of alkaline phosphatase, alanine and aspartate aminotransferase, γ-glutamyl transferase and/or lactic dehydrogenase. Discontinuation of the drug generally resulted in a return to or toward normal concentrations of these specific parameters.
Additional tissues less commonly affected in the various studies included the stomach, thymus and other lymphoid tissues and the kidneys. Conjunctival injection and lacrimation, following near therapeutic dosages, occurred in dogs only. At a massive dosage of 400 mg/kg/day, some dogs and monkeys developed corneal opacities and/or edema.
Fertility, Reproduction and Teratogenicity: Fertility and reproduction studies have shown daily dosages of 150-160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition and number and viability of offspring. Two (2) teratogenicity studies in both Wistar (oral) and Sprague-Dawley (oral and IV) rats, 1 study in New Zealand White rabbits and 1 study in cynomolgus monkeys failed to demonstrate any teratogenicity from clarithromycin. Only in 1 additional study in Sprague-Dawley rats at similar doses and essentially similar conditions did a very low, statistically insignificant incidence (approximately 6%) of cardiovascular anomalies occur. These anomalies appeared to be due to spontaneous expression of genetic changes within the colony. Two (2) studies in mice also revealed a variable incidence of cleft palate (3-30%) following doses of 70 times the upper range of the usual daily human clinical dose (500 mg twice daily), but not at 35 times the maximal daily human clinical dose, suggesting maternal and fetal toxicity but not teratogenicity.
Clarithromycin has been shown to produce embryonic loss in monkeys when administered at approximately 10x the upper range of the usual daily human dose (500 mg twice daily), starting at gestation day 20. This effect has been attributed to maternal toxicity of the drug at very high doses. An additional study in pregnant monkeys at dosages of approximately 2.5-5 times the maximal intended daily dosage produced no unique hazard to the conceptus.
A dominant lethal test in mice given 1,000 mg/kg/day (approximately 70 times the maximal human daily clinical dose) was clearly negative for any mutagenic activity and in a segment I study of rats treated with up to 500 mg/kg/day (approximately 35 times the maximal daily human clinical dose) for 80 days, no evidence of functional impairment of male fertility due to this long-term exposure to these very high doses of clarithromycin was exhibited.
Mutagenicity: Studies to evaluate the mutagenic potential of clarithromycin were performed using both non-activated and rat liver-microsome-activated test systems (Ames Test). Results of these studies provided no evidence of mutagenic potential at drug concentrations of ≤25 mcg/Petri plate. At a concentration of 50 mcg the drug was toxic for all strains tested.
Microbiology: Clarithromycin has demonstrated excellent in vitro activity against both standard strains of bacteria and clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally one log2 dilution more potent than the MICs of erythromycin.
In vitro data also indicate clarithromycin has excellent activity against Legionella pneumophila and Mycoplasma pneumonia. It is bactericidal to Helicobacter pylori; this activity of clarithromycin is greater at neutral pH than at acid pH. In vitro and in vivo data show this antibiotic has activity against clinical significant mycobacterial species.
The in vitro data indicate Enterobacteriaceae, pseudomonas species and other non-lactose fermenting gram-negative bacilli are not susceptible to clarithromycin.
Clarithromycin has been shown to be active against most strains of the following organisms both in vitro and in clinical infections as described in Indications.
Aerobic Gram-Positive Microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic Gram-Negative Microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.
Other Microorganisms: Mycoplasma pneumonia, Chlamydiapneumoniae (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium avium complex (MAC) consisting of; Mycobacterium avium, Mycobacterium intracellulare.
β-lactamase production should have no effect on clarithromycin activity.
Note: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.
Helicobacter: Helicobacter pylori: In cultures performed prior to therapy, H. pylori was isolated and clarithromycin MIC's were determined pretreatment in 104 patients. Of these, 4 patients had resistant strains, 2 patients had strains with intermediate susceptibility and 98 patients had susceptible strains.
The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic Gram-Positive Microorganisms: Streptococcus agalactiae, Streptococci (Group C,F,G), Viridans group streptococci.
Aerobic Gram-Negative Microorganisms: Bordetella pertussis, Pasteurella multocida.
Anaerobic Gram-Positive Microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic Gram-Negative Microorganisms: Bacteroides melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni.
The principal metabolite of clarithromycin in man and other primates is a microbiologically-active metabolite, 14-(OH)-clarithromycin. This metabolite is as active or 1- to 2-fold less active than the parent compound for most organisms, except for H. influenzae against which it is twice as active. The parent compound and the 14-OH metabolite exert either an additive or synergistic effect on H. influenzae in vitro and in vivo, depending on bacterial strains.
Clarithromycin was found to be 2-10 times more active than erythromycin in several experimental animal infection models. It was shown, for example, to be more effective than erythromycin in mouse systemic infection, mouse SC abscess and mouse respiratory tract infections caused by S. pneumoniae, S. aureus, S. pyogenes and H. influenzae. In guinea pigs with Legionella infection this effect was more pronounced; an intraperitoneal dose of 1.6 mg/kg/day of clarithromycin was more effective than 50 mg/kg/day of erythromycin.
Susceptibility Tests: Quantitative methods that require measurement of zone diameters give the most precise estimates of susceptibility of bacteria to antimicrobial agents. One recommended procedure uses discs impregnated with 15 mcg of clarithromycin for testing susceptibility (Kirby-Bauer diffusion test); interpretations correlate inhibition zone diameters of this disc test with MIC values for clarithromycin. The MIC's are determined by the broth or agar dilution method.
With these procedures, a report from the laboratory of "susceptible" indicates the infecting organism is likely to respond to therapy. A report of "resistant" indicates the infective organism is not likely to respond to therapy. A report of "Intermediate Susceptibility" suggests the therapeutic effect of the drug may be equivocal or the organism would be susceptible if higher doses were used. (Intermediate susceptibility is also referred to as moderately susceptible.)

Treatment of infections caused by ≥1 susceptible organisms including lower respiratory tract infections eg, acute and chronic bronchitis and pneumonia, and upper respiratory tract infections eg, sinusitus and pharyngitis.
Initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens (see Pharmacology: Microbiology under Actions).
Skin and soft tissue infections of mild to moderate severity.
For the eradication of Helicobacter pylori in patients with proven duodenal ulcers, in the presence of acid suppression effected by omeprazole.

Adults and Children >12 years: Respiratory Tract/Skin and Soft Tissue Infections: 250 mg twice daily for 7 days although this may be increased to 500 mg twice daily for up to 14 days in severe infections.
Children >12 years: As for adults. <12 years: Clarithromycin suspension should be used.
Eradication of H. pylori: Triple Therapy Regimen: Clarithromycin 500 mg twice daily in conjunction with amoxicillin 1,000 mg twice daily and a proton pump inhibitor in standard dose twice daily for 7 days.
Dual Therapy Regimen: Clarithromycin 500 mg 3 times daily in conjunction with omeprazole 40 mg once daily for 14 days, followed by omeprazole 40 mg once daily for an additional 14 days. Supportive studies have been conducted with omeprazole 40 mg once daily for 14 days.
Elderly: As for adults.
Renal Impairment: In patients with renal impairment with creatinine clearance (CrCl) <30 mL/min, the dosage of clarithromycin should be reduced by ½ ie, 250 mg once or twice daily in more severe infections. Treatment should not be continued >14 days in these patients.
Administration: Klerimed may be given without regard to meals as food does not affect the extent of bioavailability.

Symptoms: Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. One (1) patient who had a history of bipolar disorder ingested clarithromycin 8 g and showed altered mental status, paranoid behaviour, hypokalemia and hypoxemia.
Treatment: Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.

Hypersensitivity to clarithromycin, macrolide antibiotic drugs or any of the excipients of Klerimed.
Concomitant administration of clarithromycin and any of the following drugs is contraindicated: Astemizole, cisapride, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsades de pointes (see Interactions).
Concomitant administration of clarithromycin and ergot alkaloids (eg, ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see Interactions).
Concomitant administration of clarithromycin and oral midazolam is contraindicated (see Interactions).
Clarithromycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including Torsades de Pointes (see Precautions and Interactions).
Patients with hypokalemia (risk of prolongation of QT-time); who suffer from severe hepatic failure in combination with renal impairment.
Should not be used concomitantly with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see Precautions).
Clarithromycin (and other strong CYP3A4 inhibitors) should not be used concomitantly with colchicine in patients with renal or hepatic impairment (see Precautions and Interactions).

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.
Caution is advised in patients with severe renal insufficiency.
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur eg, anorexia, jaundice, dark urine, pruritus or tender abdomen.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. Clostridium difficile-associated diarrhea must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy.
Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.
Colchicine: There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see Interactions). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity. The dose of colchicine should be reduced in all patients receiving colchicine and clarithromycin concomitantly. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see Contraindications).
Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines eg, triazolam and midazolam IV (see Interactions).
Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesemia, bradycardia (<50 bpm) or when co-administered with other medicinal products associated with QT prolongation (see Interactions). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see Contraindications).
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 β-lactam antibiotics cannot be used (eg, allergy), other antibiotics eg, clindamycin, may be the drug of 1st choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections eg, those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris and erysipelas and in situations where penicillin treatment cannot be used.
In the event of severe acute hypersensitivity reactions eg, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS) and Henoch-Schonlein purpura clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see Interactions).
Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.
Oral Hypoglycemic Agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs eg, nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended.
Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in international normalized ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin. International normalized ratio and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
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 (eg, fluvastatin) can be considered.
Effects on the Ability to Drive and Operate Machinery: 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.
Use in pregnancy: The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first 3 months of pregnancy.
The safety of clarithromycin during pregnancy has not been established. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.
Use in lactation: The safety of clarithromycin use during breast-feeding of infants has not been established. Clarithromycin is excreted into human breast milk.
Use in children: The use of Klerimed has not been studied in children <12 years.

Use in pregnancy: The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk, particularly during the first 3 months of pregnancy.The safety of clarithromycin during pregnancy has not been established. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risk.
Use in lactation: The safety of clarithromycin use during breast-feeding of infants has not been established. Clarithromycin is excreted into human breast milk.

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics.
There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.
Table 2 displays adverse reactions reported in clinical trials and from post-marketing experience with Klerimed immediate release, granules for oral suspension, IV and modified-release (MR).
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 2.)

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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, some with a fatal outcome. Deaths have been reported in some such patients (see Contraindications, Precautions and Interactions).
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Immunocompromised Patients: In acquired immunodeficiency syndrome (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 events by patients treated with total daily doses of clarithromycin 1,000 mg were: Nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing disturbance, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) elevations. Additional low-frequency events included dyspnea, insomnia and dry mouth.
In these immunocompromised patients, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal level (ie, the extreme high or low limit) for the specified test. On the basis of this criteria, about 2-3% of these patients who received clarithromycin 1000 mg daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients also had elevated blood urea nitrogen levels.

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Cisapride, pimozide, astemizole and terfenadine.
Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly.
This may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
Macrolides have been reported to alter the metabolism of terfenadine resulting in increased levels of terfenadine which has occasionally been associated with cardiac arrhythmias eg, QT prolongation, ventricular tachycardia, ventricular fibrillation and Torsades de pointes (see Contraindications). In 1 study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a 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 ischemia of the extremities and other tissues, including the central nervous system (CNS). Concomitant administration of clarithromycin and ergot alkaloids is contraindicated (see Contraindications).
Effects of Other Medicinal Products on Clarithromycin: Drugs that are inducers of CYP3A (eg, 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 inhibitor 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 (CYP450) metabolism system eg, 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 8 hrs and clarithromycin 500 mg every 12 hrs resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin peak plasma concentration (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 creatinine clearance (CrCl) 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CrCl <30 mL/min, the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin >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: Antiarrhythmics: There have been post-marketed reports of Torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of these medications should be monitored during clarithromycin therapy.
CYP3A-based Interactions: Co-administration of clarithromycin, known to inhibit CYP3A and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (eg, carbamazepine) and/or the substrate is extensively metabolized by this enzyme. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.
The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: Alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the CYP450 system include phenytoin, theophylline and valproate.
Omeprazole: Clarithromycin (500 mg every 8 hrs) 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_½ increased by 30%, 89% and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hr gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.
Sildenafil, Tadalafil, and Vardenafil: Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.
Theophylline, Carbamazepine: Results of clinical studies indicate there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these drugs were administered concomitantly with clarithromycin.
Tolterodine: The primary route of metabolism for tolterodine is via the 2D6 isoform of CYP450 (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 eg, clarithromycin in the CYP2D6 poor metabolizer population.
Triazolobenzodiazepines (eg, Alprazolam, Midazolam, Triazolam): When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after IV administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If midazolam IV is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and CNS effects (eg, 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 (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are administered together, inhibition of P-gp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine.
Patients should be monitored for clinical symptoms of colchicine toxicity. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function.
Concomitant use of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see Contraindications and Precautions).
Digoxin: Digoxin is thought to be a substrate for the efflux transporter, P-gp. Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are administered together, inhibition of P-gp 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. This interaction does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine.
Phenytoin and Valproate: There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with drugs metabolized by CYP450 isoforms other than CYP3A (eg, phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Bi-Directional Drug Interactions: Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (CrCl 30-60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with CrCl <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin >1,000 mg/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 (eg, 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 bi-directional 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, 1,200 mg 3 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 2 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 previous text).
Incompatibilities: Not applicable.

Store below 25°C.
Shelf-Life: 36 months.

Macrolides

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

POM