Approval date: June 27, 2007
Date of revision: xxxx, xx, xx, xx
Clarithromycin extended-release tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Clarithromycin extended-release tablets
Trade name: Clarithromycin® Klacid® SR
English name: Clarithromycin Sustained Release Tablets
Hanyu Pinyin：Kelameisu Huanshipian
Ingredients
The main ingredient of this product is clarithromycin.
Chemical name: 6-O-methylerythromycin
Chemical structure formula
Molecular formula: C38H69NO13
Molecular weight: 747.96
Excipients: Citric acid anhydrous, sodium alginate, calcium sodium alginate, lactose, povidone K30, talc, stearic acid, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol 400, polyethylene glycol 8000, titanium dioxide, dye yellow (E104), sorbic acid
Properties
This product is a yellow film-coated tablet, after removing the coating, it appears white or off-white.
Indications
Clarithromycin extended-release tablets are used for the treatment of infections caused by pathogenic bacteria that are sensitive to them. Including.
Lower respiratory tract infections: acute and chronic bronchitis and pneumonia; caused by Haemophilus influenzae, Haemophilus parainfluenzae, Catamorax, Streptococcus pneumoniae, Legionella pneumophila, Bacillus pertussis, Staphylococcus aureus, Mycoplasma pneumoniae or Chlamydia pneumoniae.
Upper respiratory tract infections: sinusitis and pharyngitis; caused by Streptococcus pyogenes, Haemophilus influenzae, Catamorax, Streptococcus pneumoniae, Streptococcus straw green, gonococcus, Staphylococcus aureus, anaerobic bacteria, etc.
Mild to moderate infections of the skin and soft tissues: folliculitis, cellulitis, and dermatitis; caused by Staphylococcus aureus, Streptococcus pyogenes, Propionibacterium acnes, Streptococcus griseus, etc.
For the in vitro antibacterial spectrum of Clarithromycin, see [Pharmacology and Toxicology].
Specification】 0.5g
Dosage
Adults: The general recommended dose of Clarithromycin extended-release tablets is 1 tablet (0.5g) once a day with food. In severe infections, the dose may be increased to 2 tablets a day. The course of treatment is usually 7~14 days.
Children over 12 years of age: same as adults.
Children under 12 years of age: Use suspension or suspension granules.
Clarithromycin extended-release tablets are contraindicated in patients with renal insufficiency (creatinine clearance <30mL/min). Clarithromycin immediate-release tablets may be used in this patient group (see [Contraindications]). In patients with moderately impaired renal function (creatinine clearance of 30-60 mL/min), the dose should be reduced by 50% to a maximum dose of 1 Clarithromycin Immediate Release Tablet per day.
[Adverse Reactions].
Clarithromycin is well tolerated. The most frequent and common adverse reactions to clarithromycin in adults and children are abdominal pain, diarrhea, nausea, vomiting, and abnormal taste. These adverse reactions are usually mild and are consistent with the known safety information for macrolide antibiotics. Clinical trials have found no significant difference in the incidence of gastrointestinal adverse reactions in patients with pre-existing Mycobacterium avium infection compared to those without.
Dental discoloration has been reported following treatment with clarithromycin. Tooth discoloration is generally reversible after professional dental cleaning.
Clinical trials and post-marketing reports of adverse reactions to clarithromycin extended-release tablets are categorized by frequency of occurrence as follows.
Common (frequency of occurrence ≥ 1/100 to <1/10): insomnia, taste disturbance, headache, abnormal taste, diarrhea, vomiting, dyspepsia, nausea, abdominal pain, abnormal liver function tests, skin rash, excessive sweating.
Uncommon (occurring ≥1/1,000 to <1/100): candidiasis, gastroenteritis, vaginal infection, leukopenia, hypersensitivity reactions, anorexia, decreased appetite, anxiety, dizziness, drowsiness, tremor, vertigo, hearing impairment, tinnitus, prolonged ECG QT interval, palpitations, epistaxis, gastroesophageal reflux disease, gastritis, analgia, stomatitis, tongue inflammation, constipation, dry mouth, belching flatulence, elevated alanine aminotransferase, elevated aspartate aminotransferase, pruritus, urticaria, myalgia, weakness.
Unknown (frequency of occurrence cannot be assessed on the basis of available data)*: pseudomembranous colitis, dermatitis, granulocyte deficiency, thrombocytopenia, allergic reaction, angioedema, psychiatric disorder, confused state of consciousness, depression, disorientation, hallucinations, dream abnormalities, mania, convulsions, loss of taste, olfactory abnormalities, loss of smell, sensory abnormalities, loss of hearing, tip-twisting ventricular tachycardia, ventricular tachycardia, ventricular fibrillation, hemorrhage, acute pancreatitis, tongue discoloration, tooth discoloration, liver failure, hepatocellular jaundice, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne, rhabdomyolysis**, myopathy, renal failure, interstitial nephritis, international normalized ratio (INR) International normalized ratio (INR) elevation, prolonged prothrombin time, abnormal urine color.
*Since these reactions were reported from a population of uncertain size, it is not always possible to reliably evaluate their frequency or to establish a causal relationship with drug exposure. Patient exposure to clarithromycin is estimated to exceed 1 billion patient treatment days.
**In some rhabdomyolysis case reports, clarithromycin was administered in combination with statins, fibrates, colchicine, and allopurinol.
Immunocompromised Patients
In patients with AIDS and other immunocompromised patients on long-term use of higher doses of clarithromycin for the treatment of mycobacterial infections, it is difficult to distinguish whether adverse events may be related to clarithromycin administration or signs or complications of human immunodeficiency virus (HIV) disease.
In adult patients, the most common adverse reactions at a total daily dose of clarithromycin of 1000 mg include nausea, vomiting, altered taste, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, and elevated serum glutamic oxalacetic transaminase (SGOT) and serum glutamic acid transaminase (SGPT). In addition, infrequent adverse reactions include dyspnea, insomnia, and dry mouth.
In immunocompromised patients, the evaluation of some specific laboratory findings is based on the analysis of significantly abnormal values (e.g., very high or very low values). Based on these criteria, approximately 2% to 3% of patients taking 1000 mg of clarithromycin daily have severely abnormally elevated SGOT and SGPT levels and abnormally low white blood cell and platelet counts. In addition, a lower percentage of patients will have elevated blood urea nitrogen levels.
[Contraindications
This product is contraindicated in patients with known hypersensitivity to macrolide antibiotics or their excipients.
The combination of clarithromycin with the following drugs is prohibited: Astemizole, cisapride, pimozide, and terfenadine. The combination of clarithromycin with these drugs may cause prolongation of the QT interval and arrhythmias, including ventricular tachycardia, ventricular fibrillation, and tip-twisting ventricular tachycardia.
Combination of clarithromycin with ergotamine or dihydroergotamine is prohibited as it may lead to ergometrine toxicity.
Combination of clarithromycin with oral midazolam is contraindicated.
Clarithromycin should not be administered to patients with a history of prolonged QT interval or ventricular arrhythmias, including tip-twisting ventricular tachycardia.
Clarithromycin is contraindicated in patients with hypokalemia (risk of QT interval prolongation).
Clarithromycin is contraindicated in patients with severe hepatic insufficiency associated with renal insufficiency.
Clarithromycin should not be combined with HMG-CoA reductase inhibitors (statins: lovastatin or simvastatin), which are metabolized primarily by CYP3A4, or there may be a risk of rhabdomyolysis.
The combination of clarithromycin (and other potent inhibitors of CYP3A4) with colchicine is prohibited.
This product is contraindicated in patients with creatinine clearance <30mL/min because the daily dose cannot be less than 500mg. Clarithromycin rapid release tablets may be used in such patients.
Clarithromycin is contraindicated in combination with ticagrelor or ranolazine.
Precautions]
Doctors must carefully weigh the pros and cons before using clarithromycin in women during pregnancy, especially in the third trimester.
As with other antibiotics, prolonged use of this product may result in increased numbers and colonization by non-susceptible bacteria and fungi. If a secondary infection occurs, appropriate treatment should be administered.
It is recommended that this product be used with caution in patients with severe renal insufficiency.
Cases of abnormal liver function, including elevated liver enzymes, hepatocellular damage and/or hepatic cholestasis, with or without jaundice, have been reported with treatment with clarithromycin. Such abnormalities of liver function may be severe, but are usually reversible. Fatal liver failure has been reported, and this is usually associated with severe underlying disease and/or comorbid medication use. If signs and symptoms of liver disease develop, such as anorexia, jaundice, dark urine, itching, or abdominal pressure, patients are advised to discontinue therapy and seek medical attention.
Pseudomembranous colitis has been reported with almost all antimicrobial agents (including macrolides) and ranges from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported for most antimicrobials, including clarithromycin, and ranges from mild diarrhea to fatal colitis. Antimicrobial drug therapy can alter the normal colonic flora, which may lead to C. difficile overgrowth. The possibility of C. difficile-associated diarrhea must be considered in all patients who develop diarrhea following the use of antibiotic medications. Since C. difficile-associated diarrhea has been reported after more than two months of antimicrobial therapy, the patient’s medical history must be carefully reviewed.
Clarithromycin is primarily metabolized by the liver. Therefore, this product should be used with caution in patients with hepatic impairment. Clarithromycin should be used with caution in patients with moderate to severe renal impairment.
Colchicine: Post-marketing reports also indicate that colchicine toxicity occurs when colchicine and clarithromycin are combined, particularly in the elderly, and in some cases in patients with renal insufficiency. Some of these patients died. Clarithromycin is contraindicated in combination with colchicine.
Caution is recommended when combining clarithromycin with triazolam benzodiazepines such as triazolam, midazolam administered intravenously or via the oral mucosa.
Because of the risk of QT interval prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesemia, bradycardia (<50 bpm), and caution must be exercised when combining other drugs associated with QT interval prolongation. Clarithromycin should not be administered to patients with known congenital or acquired QT interval prolongation, or a history of ventricular arrhythmias.
QT interval prolongation: Cardiac repolarization and QT interval prolongation have been observed in macrolide therapy, thereby raising the risk of arrhythmias and tip-twisting ventricular tachycardia, so caution is warranted when treating patients who
● Patients on other active substances known to prolong the QT interval (e.g., class IA and III antiarrhythmics, antipsychotics, antidepressants, and fluoroquinolones)
● Patients with electrolyte disturbances, especially hypomagnesemia
● Patients with clinically relevant bradycardia or cardiac insufficiency
● Elderly patients: elderly patients may be more sensitive to drug-induced effects on the QT interval
Pneumonia.
Because some Streptococcus pneumoniae appear resistant to macrolides, susceptibility testing is important when prescribing clarithromycin for community-acquired pneumonia. If empiric treatment is clinically ineffective, antibiotic susceptibility testing should be considered and adjusted to a sensitive antibiotic for treatment. In the case of hospital-acquired pneumonia, clarithromycin needs to be used in combination with other appropriate antibiotics.
Mild to moderate skin and soft tissue infections.
These infections are usually caused by Staphylococcus aureus and Streptococcus pyogenes, which may be resistant to macrolide antibiotics. Therefore it is important to implement susceptibility testing. If empiric treatment is clinically ineffective, antibiotic susceptibility testing should be considered and treatment should be adjusted to a sensitive antibiotic. In cases where β-lactam antibiotics cannot be used (e.g., allergy), other antibiotics, such as clindamycin, should be chosen. Currently, macrolides are considered effective for some skin and soft tissue infections, such as infections caused by Corynebacterium minimalis, acne vulgaris, dermatitis, and infections that cannot be treated with penicillin.
In case of severe acute hypersensitivity reactions (e.g., allergic reactions, Stevens-Johnson’s syndrome and toxic epidermal necrolysis, DRESS syndrome (drug rash with eosinophilia and systemic symptoms)), clarithromycin must be discontinued immediately and appropriate treatment implemented urgently.
Caution should be exercised when combining clarithromycin if the patient is currently taking drugs that induce cytochrome CYP3A4 enzymes.
Cross-resistance between clarithromycin and other macrolides and between lincomycin and clindamycin should also be noted.
HMG-CoA reductase inhibitors: Combination of clarithromycin with lovastatin or simvastatin is prohibited. Caution is required when clarithromycin is combined with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. However, it is not possible to avoid the need to monitor patients for signs and symptoms of myopathy when the two are combined. A minimum dose of a statin is also recommended. Statins that are not dependent on CYP3A metabolism (e.g., fluvastatin) should be considered.
Oral hypoglycemic agents/insulin: Concomitant use of clarithromycin with oral hypoglycemic agents (e.g., sulfonylureas) and/or insulin may result in significant hypoglycemia. Careful monitoring of the patient’s blood glucose is recommended.
Oral anticoagulants.
Concomitant use of clarithromycin with warfarin may result in severe bleeding and significant elevation of INR and prothrombin time. Therefore, INR and prothrombin time should be monitored closely when patients are using clarithromycin and oral anticoagulants together.
Clarithromycin extended-release tablets contain lactose. They are contraindicated in patients with rare genetic problems such as galactose intolerance, lactase deficiency, or glucose/galactose absorption disorder syndrome.
[For pregnant and lactating women].
The safety of clarithromycin during pregnancy and lactation has not been confirmed. Therefore, clarithromycin should not be used during pregnancy and lactation unless the physician believes that the benefits outweigh the risks. Some animal studies have shown that clarithromycin has embryotoxic effects, but this only occurs at dose levels that are significantly toxic to the mother. Clarithromycin has been detected in animal and human breast milk.
Pediatric Use
Please refer to [Dosage].
Geriatric use
Please refer to [Precautions].
Effect on driving and machine operation].
There is no data to suggest that clarithromycin may affect driving or machine operation. Dizziness, dizziness, confusion and disorientation may occur with the use of this product, so patients should consider possible adverse effects after taking the drug before driving or using machines.
Drug Interactions]
The use of the following drugs is absolutely contraindicated due to the potentially serious effects caused by their pharmacological interactions.
Cisapride, pimozide, astemizole and terfenadine
Elevated levels of cisapride have been reported in patients co-administered with cisapride and clarithromycin. Concomitant administration may result in prolonged QT intervals, arrhythmias including ventricular tachycardia, ventricular fibrillation and tip-twist ventricular tachycardia, and similar effects have been observed in patients co-administered with clarithromycin and pimozide.
It has been reported in the literature that macrolide antibiotics can affect the metabolism of terfenadine, thereby increasing its blood levels and occasionally leading to arrhythmias such as prolonged QT interval, ventricular tachycardia, ventricular fibrillation and tip-twisting ventricular tachycardia. In a study of 14 healthy volunteers, concomitant use of clarithromycin and terfenadine resulted in a 2- to 3-fold increase in blood concentrations of the acidic metabolite of terfenadine and prolongation of the QT interval, but no detectable clinical response. Similar interactions have been observed with the combination of astemizole and other macrolides.
Ergot alkaloids
Postmarketing reports suggest that the combination of clarithromycin and ergotamine or dihydroergotamine is associated with acute ergot alkaloid toxicity, manifested by vasospasm and ischemia in the extremities and other tissues, including the central nervous system. The combination of clarithromycin with these drugs is contraindicated.
Oral Midazolam
When midazolam is combined with clarithromycin tablets (500 mg twice daily), the area under the drug-time curve (AUC) after oral administration of midazolam is increased 7-fold. Therefore, the combination of oral midazolam with clarithromycin is prohibited.
HMG-CoA reductase inhibitors (statins)
The combination of clarithromycin with lovastatin or simvastatin is prohibited. Concomitant use of clarithromycin and lovastatin or simvastatin can result in elevated plasma concentrations of these statins as they are extensively metabolized by CYP3A4, which increases the risk of myopathy, including rhabdomyolysis.
Cases of rhabdomyolysis have been reported in patients who have been co-administered clarithromycin with these statins. If treatment with clarithromycin is unavoidable, lovastatin or simvastatin should be withheld for the duration of treatment.
Caution should be exercised when combining clarithromycin with a statin. In cases where combination of clarithromycin and statins is unavoidable, the lowest dose of statin available on record is recommended. Statins that are not dependent on CYP3A metabolism (e.g., fluvastatin) should be considered. Patients should be monitored for signs and symptoms of myopathy.
Effects of other drugs on clarithromycin
CYP3A-inducing drugs (rifampin, phenytoin, carbamazepine, phenobarbital, and gentamicin) can induce the metabolism of clarithromycin. This leads to a reduction in the therapeutic level and efficacy of clarithromycin.
In addition, it is necessary to monitor the plasma concentration of CYP3A inducers, which may be elevated by the inhibition of CYP3A by clarithromycin (see the instructions for CYP3A inhibitors).
Combined administration of rifabutin and clarithromycin can result in increased serum levels of rifabutin and decreased serum levels of clarithromycin, associated with an increased risk of uveitis.
The following drugs have been shown or are suspected to affect clarithromycin blood levels; it is necessary to adjust the dose of clarithromycin or consider the possibility of alternative therapy
Efavirenz, nevirapine, rifampin, rifabutin, and rifapentine
Strong inducers of the cytochrome P450 metabolic system, such as efavirenz, nevirapine, rifampin, rifabutin, and rifapentine accelerate the metabolism of clarithromycin, thereby decreasing the plasma levels of clarithromycin while increasing the plasma levels of 14-hydroxyclarithromycin, a metabolite that also has microbial activity. Because the microbial activity of clarithromycin and 14-hydroxyclarithromycin is different for different bacteria, the therapeutic effect is diminished more than expected during concomitant administration of clarithromycin and enzyme inducers.
Etravirine
Etravirine results in reduced exposure to clarithromycin and increased concentrations of the active metabolite 14-hydroxyclarithromycin. Since 14-hydroxyclarithromycin decreases the activity against Mycobacterium avium-intracellulare complex (MAC) and the overall activity against this pathogen is altered, it is necessary to evaluate the therapeutic regimen of clarithromycin selection in the treatment of Mycobacterium avium-intracellulare complex (MAC).
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in a 33% and 18% increase in mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC), respectively. The combination of fluconazole did not significantly affect the steady-state concentration of the active metabolite 14-hydroxyclarithromycin. No adjustment of clarithromycin dose was required.
Ritonavir
Pharmacokinetic studies have shown that concomitant administration of ritonavir (200 mg every 8 hours) and clarithromycin (500 mg every 12 hours) significantly inhibits clarithromycin metabolism. When both drugs were administered concomitantly, the maximum concentration (Cmax) of clarithromycin increased by 31%, the minimum concentration (Cmin) increased by 182%, and the area under the blood concentration curve (AUC) increased by 77%. Complete inhibition of 14-hydroxyclarithromycin formation was also observed.
Due to the large therapeutic window of clarithromycin, there is no need to reduce the dose of the drug if the patient has normal renal function. However, in patients with impaired renal function who are treated with concomitant ritonavir, the following dose adjustment regimen should be considered: if the patient’s creatinine clearance is between 30 ml/min and 60 ml/min, the dose of clarithromycin should be reduced by 50%; if the patient’s creatinine clearance is below 30 ml/min, the drug dose should be reduced by 75%. When administered concomitantly with ritonavir, care should be taken to avoid a daily dose of clarithromycin exceeding 1000 mg.
Similar dose adjustments should be considered when ritonavir is used as a pharmacologic booster for other HIV protease inhibitors (e.g., atazanavir and saquinavir) in patients with decreased renal function (see Bidirectional Drug Interactions).
Clarithromycin’s effect on other drugs
Antiarrhythmics
There are marketing reports of cases of tip-twisting ventricular tachycardia following the combination of clarithromycin and quinidine or propyzamide. Electrocardiographic (ECG) monitoring should be performed in combination with clarithromycin to detect potential QT interval prolongation, and serum concentrations of these drugs should be monitored during treatment.
There have been cases of hypoglycemia following the combination of clarithromycin and propyzamide in post-marketing reports. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and propyzamide.
Oral hypoglycemic agents/insulin
The inhibition of CYP3A enzymes by clarithromycin may lead to hypoglycemia in the setting of combined clarithromycin and some glucose-lowering agents such as pioglitazone, rosiglitazone, nateglinide, and repaglinide. Careful monitoring of blood glucose levels is recommended.
CYP3A-based interactions
Clarithromycin is known to inhibit CYP3A and its combination with drugs that are primarily metabolized by CYP3A increases the concentration of this drug and may increase or prolong the efficacy and adverse effects of the drug.
Clarithromycin should be used with caution when taking other known substrates of CYP3A enzymes, especially if the drug has a narrow safety range (e.g., carbamazepine) and/or the drug is extensively metabolized by this enzyme.
Dose adjustments may be considered and, where possible, serum concentrations of drugs metabolized primarily by CYP3A should be closely monitored in patients co-administering clarithromycin.
The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, propyzamide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g., warfarin), atypical antipsychotics (e.g., quetiapine), pimozide, quinidine rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vincristine. This list is not comprehensive. Other drugs that cause interactions by similar mechanisms from isozymes within the cytochrome P450 system include phenytoin, theophylline, and valproic acid.
Omeprazole
Concomitant administration of clarithromycin (500 mg every 8 hours) and omeprazole (40 mg daily) was given to healthy adult subjects. Steady-state plasma concentrations of omeprazole were elevated due to concomitant administration with clarithromycin (Cmax, AUC0-24 and t1/2 by 30%, 89% and 34%, respectively).
When omeprazole was administered alone or when omeprazole was administered concomitantly with clarithromycin, the mean 24-hour gastric pH was 5.2 and 5.7, respectively.
Sildenafil, tadalafil and vardenafil
These phosphodiesterase inhibitors are all metabolized by or at least partially by CYP3A, which is inhibited when clarithromycin is co-administered. The combination of clarithromycin with sildenafil, tadanafil, or vardenafil results in increased exposure to phosphodiesterase inhibitors. Therefore, lower doses of sildenafil, tadanafil, and vardenafil should be considered when these drugs are used concomitantly with clarithromycin.
Theophylline, carbamazepine
Clinical studies have shown a small but statistically significant (p ≤ 0.05) increase in blood levels of carbamazepine and theophylline when either of these drugs is administered concomitantly with clarithromycin.
Tolterodine
Tolterodine is metabolized primarily via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in the subgroup of the population lacking CYP2D6, the primary metabolic pathway is via CYP3A. In this population subgroup, inhibition of CYP3A results in a significant increase in tolterodine serum concentrations. Dose reductions of tolterodine may be required in the presence of CYP3A inhibitors, such as when co-administering clarithromycin in a population of patients with weak CYP2D6 metabolism.
Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
When midazolam was administered concomitantly with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous midazolam. If intravenous midazolam is administered concomitantly with clarithromycin, the patient should be closely monitored for dose adjustment. If midazolam is administered via the oral mucosa, it may bypass circulating pre-drug elimination, a situation similar to that of midazolam administered intravenously compared to oral administration. The same precautions apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines that are not metabolized by CYP3A (temazepam, nitrazepam, lorazepam), there are no clinically significant interactions with clarithromycin.
Postmarketing reports of drug interactions and CNS effects (e.g., drowsiness and confusion) have been reported with clarithromycin in combination with triazolam. Monitoring for enhanced central nervous system (CNS) pharmacologic effects is recommended.
Other drug interactions
Colchicine
Colchicine is a substrate for CYP3A and the transporter P-glycoprotein (Pgp). Clarithromycin and other macrolides inhibit CYP3A and Pgp. Combined use of clarithromycin and colchicine increases colchicine exposure because clarithromycin inhibits Pgp and/or CYP3A. Therefore, concomitant use of clarithromycin and colchicine is prohibited.
Digoxin
Digoxin is a substrate for the transporter Pgp. Clarithromycin inhibits Pgp. When digoxin and clarithromycin are used together, the inhibition of Pgp by clarithromycin leads to increased exposure to digoxin. Elevated serum concentrations of digoxin have also been reported in patients on concomitant clarithromycin and digoxin in post-marketing surveillance. Some patients exhibited clinical signs consistent with digoxin toxicity, including potentially fatal cardiac arrhythmias. Patients should be closely monitored for digoxin serum concentrations when combining digoxin and clarithromycin.
Zidovudine
In adult patients with HIV infection, concomitant oral administration of clarithromycin and zidovudine may decrease the steady-state concentration of zidovudine. Clarithromycin may interfere with the absorption of zidovudine when the two drugs are taken orally at the same time, and taking the two drugs at different times may largely avoid this interaction. In HIV-infected pediatric patients, concomitant administration of clarithromycin dry suspension and zidovudine or desoximetasone does not produce such an interaction. Similar interaction studies have not been conducted for the combination of clarithromycin extended-release tablets and zidovudine.
Phenytoin and Valproic Acid
There have been spontaneous or published reports of interactions of CYP3A inhibitors (including clarithromycin) with drugs that are metabolized by cytochrome P450 subunits even more than CYP3A (e.g., phenytoin and valproic acid). Elevated serum levels have been reported. It is recommended that serum levels be measured when these drugs are combined with clarithromycin.
Bidirectional drug interactions
Atazanavir
Clarithromycin and atazanavir are both substrates and inhibitors of CYP3A and have bidirectional drug interactions. The combination of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) resulted in a 2-fold increase in clarithromycin exposure, a 70% decrease in 14-hydroxyclarithromycin exposure, and a 28% increase in atazanavir AUC. Due to the wide therapeutic window of clarithromycin, no reduction in dose administration is required for patients with normal renal function. In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance less than 30 ml/min, the appropriate clarithromycin formulation should be selected and the dose reduced by 75%. Clarithromycin should not be used in combination with protease inhibitors at doses above 1000 mg daily.
Calcium channel blockers
Due to the risk of hypotension, caution is advised when combining clarithromycin with CYP3A4-metabolized calcium channel blockers (e.g., verapamil, amlodipine, diltiazem). Drug interactions can result in elevated blood levels of clarithromycin and calcium channel blockers. Symptoms of hypotension, bradycardia, and lactic acidosis have been observed in patients on combined clarithromycin and verapamil.
Itraconazole
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to bidirectional drug interactions. Clarithromycin can elevate plasma levels of itraconazole, and itraconazole can also elevate plasma levels of clarithromycin. Patients combining clarithromycin and itraconazole should be closely monitored for signs or symptoms of enhanced or prolonged pharmacologic effects.
Saquinavir
Clarithromycin and saquinavir are both substrates and inhibitors of CYP3A, and there are bidirectional drug interactions. 12 healthy volunteers co-administered clarithromycin (500 mg twice daily) and saquinavir (softgels, 1200 mg three times daily) resulted in steady-state AUCs and Cmaxs that were 177% and 187% higher, respectively, for saquinavir than for clarithromycin alone, and AUCs and Cmax were approximately 40% higher than when used alone. No dose adjustment was required for the combined administration of the two drugs for the limited time period at the doses and dosage forms studied here. The results of drug interaction studies using saquinavir softgels may not be representative of saquinavir hardgels. The results of drug interaction studies with saquinavir alone may not be representative of the effects of saquinavir/ritonavir therapy. The potential effect of ritonavir on clarithromycin needs to be considered when saquinavir and ritonavir are combined. [Drug Overdose].
Gastrointestinal adverse reactions may occur if too high a dose of clarithromycin is ingested. A patient with bipolar disorder developed altered mental status, paranoia, hypokalemia, and hypoxemia after ingesting 8 grams of clarithromycin.
Once an overdose of clarithromycin is detected, the unabsorbed drug should be removed immediately and appropriate supportive therapy should be initiated. Similar to other macrolides, the serum concentration of clarithromycin is not affected by hemodialysis or peritoneal dialysis.
Pharmacology and Toxicology
Pharmacological effects
Clarithromycin is 6-O-methyl-erythromycin A, a semi-synthetic macrolide antibiotic, which produces antibacterial effects by binding to the ribosomal 50S subunit of bacteria sensitive to it and inhibiting its protein synthesis. Studies have shown that the drug has good in vitro antibacterial activity against both standard bacterial strains and clinical isolates. It has potent antibacterial activity against a wide range of aerobic and anaerobic Gram-positive or Gram-negative bacteria. The minimum inhibitory concentrations (MICs) of clarithromycin are typically 1 log2 dilution higher than those of erythromycin. In vitro data also indicate that clarithromycin has good antibacterial activity against Legionella pneumophila and Mycoplasma pneumoniae. Its bactericidal activity against Helicobacter pylori was higher at neutral pH than at acidic pH. both in vitro and in vivo data suggest that this antibiotic has antibacterial activity against clinically significant genera of Mycobacterium spp. In vitro data indicate that Enterobacteriaceae, Pseudomonas spp. and other non-lactose-fermenting Gram-negative bacilli are not susceptible to clarithromycin.
In vitro clarithromycin usually has antibacterial activity against the following bacteria.
Aerobic gram-positive bacteria: Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Listeria monocytogenes
Aerobic gram-negative bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Catamorax; Neisseria gonorrhoeae; Legionella pneumophila
Others: Mycoplasma pneumoniae; Chlamydia pneumoniae (TWAR)
Mycobacterium bovis: Mycobacterium leprae; Mycobacterium kansasii; Mycobacterium tortugae; Mycobacterium occasionalis; Mycobacterium avium-intracellulare complex, including Mycobacterium avium and Mycobacterium intracellulare
β-lactamase has no effect on clarithromycin activity.
Note: Most methicillin-resistant and benzocillin-resistant staphylococci are also resistant to clarithromycin.
Helicobacter: Helicobacter pylori
In cultures performed prior to treatment, H. pylori was isolated from 104 primary patients and the MIC of clarithromycin was determined. of these, resistant strains, moderately sensitive strains and sensitive strains were present in 4, 2 and 98 patients, respectively, providing the following in vitro data, but their clinical significance is unclear. Clarithromycin has demonstrated in vitro antibacterial activity against most of the following strains; however, the safety and efficacy of clarithromycin in the treatment of infections caused by the above-mentioned microorganisms has not been established in clinical trials with adequate stringent controls.
Gram-positive aerobic bacteria: non-lactating streptococci; streptococci (groups C, F, G); straw green streptococci
Gram-negative aerobic bacteria: Bacillus pertussis; Pasteurella multocida
Gram-positive anaerobic bacteria: Clostridium perfringens; Peptococcus niger; Propionibacterium acnes
Gram-negative anaerobic bacteria: melanin-producing bacilli
Spirochetes: Borrelia burgdorferi; Syphilis spirochetes
Campylobacter: Campylobacter jejuni
The major metabolite of clarithromycin in humans and other primates is 14-hydroxyclarithromycin, a product with antibacterial activity. In most microorganisms, the activity of this metabolite is comparable to or only 1/2 or 1/4 that of the parent compound, but in Haemophilus influenzae it is twice as active as the parent compound. Both the parent compound and the 14-hydroxy metabolite exhibited superimposed or synergistic effects against Haemophilus influenzae in vitro and in vivo, depending on the strain.
Clarithromycin has been observed to be 2-10 times more active than erythromycin in several experimental animal infection models. For example, clarithromycin was observed to be more effective than erythromycin in systemic infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae in mice, subcutaneous abscesses in mice, and respiratory infections in mice. This effect was more pronounced in Legionella-infected guinea pigs; clarithromycin at a dose of 1.6 mg/kg/day was more effective than erythromycin at a dose of 50 mg/kg/day when administered intraperitoneally.
Toxicological studies
Genotoxicity
The results of the Ames test showed no mutagenicity at drug concentrations ≤25 μg/plate, and toxicity to all test strains at 50 μg. In a dominant lethal assay, mice receiving a dose of 1000 mg/kg/day (approximately 70 times the highest clinically available human daily dose) did not develop any mutagenic activity after administration.
Reproductive toxicity.
Results of the fertility and reproductive effects assay showed no effects on libido, fertility, number and development of births and offspring in male and female rats at doses of 150-160 mg/kg/d. Teratogenic effects of clarithromycin were not seen in teratogenic tests in Wistar rats (administered orally) and SD rats (administered orally and intravenously) and in New Zealand rabbits and macaques. Rare and statistically insignificant cardiovascular abnormalities (6%) were seen in only one additional test in SD rats, mainly due to the natural expression of genetic alterations within the population. Two mouse studies also showed cleft palate (3% to 30%) at 70 times the daily human clinical dose (500 mg, twice daily), but not at 35 times the maximum daily human clinical dose. This result suggests a gestational toxicity rather than a teratogenic effect.
Clarithromycin given to monkeys after 20 days of gestation at 10 times the daily human clinical higher dose (500 mg twice daily) resulted in abortion. This was mainly due to the gestational toxicity of the drug at very high doses. In a complementary trial, administration of 2.5 to 5 times the maximum daily dose of clarithromycin to monkeys did not endanger the embryo.
In a segment I reproductive toxicity test in rats, a dose of 500 mg/kg/d (approximately 35 times the maximum daily clinical dose in humans) was administered for 80 days and no sexual impairment was seen in male rats due to chronic administration of high doses of clarithromycin.
Pharmacokinetics
Absorption
The kinetics of extended-release clarithromycin were studied in adults after oral administration and compared with clarithromycin 250 mg and 500 mg immediate-release tablets. The degree of absorption was found to be the same at the same daily dose administered. The absolute bioavailability was approximately 50%. No minimal or unpredictable accumulation was observed and the metabolic profile of the various genera was unchanged after multiple dosing. The following in vitro and in vivo data based on equivalent absorption studies were found to be applicable to sustained release dosage forms.
Distribution, biotransformation and elimination
In vitro: In vitro studies have shown that the average protein binding of clarithromycin in human plasma is 70% at concentrations ranging from 0.45 to 4.5 μg/mL. At a concentration of 45 μg/mL the binding rate decreased to 41%, suggesting that the binding site may be saturated, but this phenomenon only occurs at concentrations well above therapeutic levels of the drug.
In vivo: Animal studies have demonstrated that clarithromycin concentrations in all tissues (except the central nervous system) are several times higher than in the circulatory system. The highest concentrations were found in liver and lung tissues with tissue to plasma concentration ratios of 10 to 20.
Normal Subjects
Clarithromycin has a nonlinear pharmacokinetic profile. The peak steady-state plasma concentrations of clarithromycin and 14-hydroxy-clarithromycin were 1.3 and 0.48 μg/mL, respectively, when patients received 500 mg of clarithromycin extended-release tablets once daily with a meal. the clearance half-lives of the prodrug and metabolites were approximately 5.3 and 7.7 hours, respectively. When the dose was increased to 1000 mg per day, the steady-state values were 2.4 μg/mL and 0.67 μg/mL, respectively. the half-life of the prototype drug at the 1000 mg dose was approximately 5.8 h, whereas the half-life of 14-hydroxyclarithromycin was approximately 8.9 h. The Tmax at both the 500 and 1000 mg doses was approximately 6 h. Under steady-state conditions, the concentration of 14-hydroxyclarithromycin increased disproportionately to the clarithromycin dose, and the apparent half-lives of clarithromycin and its hydroxylated metabolites at higher doses showed a tendency to be prolonged. Given this nonlinear pharmacokinetic profile of clarithromycin, coupled with the lower overall production of 14-hydroxylated and N-demethylated products, it suggests that the nonlinear metabolism of clarithromycin is more pronounced at higher doses.
Approximately 40% of clarithromycin is excreted in the urine and approximately 30% in the feces.
Patients
Clarithromycin and its 14-hydroxy metabolites are readily distributed to body tissues and body fluids. Limited data from a small number of patients suggest that drug concentrations in the cerebrospinal fluid (CSF) are not high after oral administration of clarithromycin (i.e., in patients with a normal blood-CSF barrier, CSF drug concentrations are only 1-2% of serum concentrations). Drug concentrations in tissues are generally several times higher than serum concentrations.
Liver damage
One study compared healthy subjects with subjects with liver damage. Subjects received 250 mg of clarithromycin immediate-release tablets twice daily for the first 2 days and a single dose of 250 mg on day 3, and no significant differences in steady-state plasma concentrations and systemic clearance of clarithromycin were observed between the two groups of subjects. In contrast, subjects with hepatic impairment had significantly lower steady-state concentrations of the 14-hydroxy metabolite. The increased renal clearance of the parent drug partially offset the decreased clearance of its 14-hydroxylated metabolite, so that steady-state concentrations of the parent drug were comparable in subjects with hepatic impairment and healthy subjects. These results suggest that no dose adjustment is required in subjects with moderate or severe hepatic impairment and normal renal function.
Renal impairment
In a study, the pharmacokinetic profile of clarithromycin 500 mg immediate-release tablets was evaluated and compared in subjects with normal and reduced renal function after multiple oral doses. The results showed that plasma concentrations, half-life, Cmax and Cmin of clarithromycin and its 14-hydroxy metabolite were higher and the AUC was greater in subjects with renal impairment, while Kelim and urinary excretion rates were reduced. The degree of difference in the above parameters correlated with the degree of renal damage, with the more severe the renal damage, the more significant the difference.
Elderly subjects
A study was also conducted to evaluate and compare the safety and pharmacokinetic profile of elderly male and female subjects with healthy young adult male subjects following multiple oral doses of clarithromycin 500 mg immediate-release tablets. Circulating plasma concentrations of the parent drug and 14-hydroxy metabolite were higher and eliminated more slowly in older subjects compared to younger subjects. However, when renal clearance was correlated with CLCR, there was no difference between the two groups. This shows that all effects on clarithromycin disposition are related to renal function and not to age.
Storage】 Seal and store in a dry place.
Package】 Aluminum-plastic package, 7 tablets/box, 14 tablets/box.
Expiration date】 36 months
Executive Standard】Imported drug registration standard: JX20060203
Approval number】Imported drug registration certificate number: H20150665
【Manufacturing Company
Company Name: ABBOTT LABORATORIES (SINGAPORE) PRIVATE LIMITED
Company Address: 1 MARITIME SQUARE #12-01 HABOURFRONT CENTRE SINGAPORE 099253 Singapore
Production House: Aesica Queenborough Limited
Production Address: Queenborough, Kent, ME11 5EL U.K. United Kingdom
Domestic Contact
Name: Abbott Trading (Shanghai) Co.
Address: 32/F, Cyrus Plaza, No.388 Nanjing West Road, Shanghai
Postal Code: 200003
Telephone number: 021-23204200
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